• Sign Up

Male Infertility


Male Infertility

Article Author:
Stephen Leslie
Article Author:
Larry Siref
Article Editor:
Moien AB Khan
Updated:
10/30/2020 8:43:22 AM
For CME on this topic:
Male Infertility CME
PubMed Link:
Male Infertility

Introduction

Infertility is usually defined as the inability of a couple to conceive even after one year of unprotected, frequent sexual intercourse.[1] It affects about 15% of all couples in the United States and at least 180 million people worldwide.[2] Male infertility is defined as the inability of a male to make a fertile female pregnant, also for a minimum of at least one year of unprotected intercourse. The male is solely responsible for about 20% 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 important that both partners are investigated for infertility and managed together. Overall, the male factor is substantially contributory in about 50% of all cases of infertility.

There are several reasons for male fertility to occur including both reversible and irreversible conditions. Other factors that could influence each of the partners could be their 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 to offer counseling for irreversible and untreatable conditions.[4] In rare cases, male infertility could be a herald to a more serious condition. 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.[5]

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) at an estimated 2% to 5%), sperm transport disorders (such as vasectomy) at 5%, primary testicular defects (which includes 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%.[6]  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. [6]  A partial summary of specific etiologies is listed below: 

  • Endocrinological cause - Congenital GnRH Deficiency (Kallmann syndrome), Prader Willi Syndrome, Laurence - Moon - Beidl syndrome, iron overload syndrome, familial cerebellar Ataxia, head trauma, intracranial radiation, testosterone supplementation or hyperthyroidism.
  • Idiopathic - Idiopathic male infertility (10% to 20%) where semen parameters are all normal but the male remains infertile.
  • Genetic causes - Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, primary ciliary dyskinesia, Kallmann syndrome, Klinefelter's 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, gr/gr deletion.
  • Congenital urogenital abnormalities - Absent, dysfunctional, or obstructed epididymis, congenital abnormalities of the vas deferens, undescended testes, ejaculatory duct disorders (cysts).
  • Acquired urogenital abnormalities - Bilateral obstruction or ligation of the vas deferens, bilateral orchiectomy, epididymitis, varicoceles, retrograde ejaculation.
  • Immunological cause - Lymphocytic hypophysitis, hemosiderosis, hemochromatosis, sarcoidosis, histiocytosis, tuberculosis, fungal infections,
  • Urogenital tract infections - Gonococci, chlamydia, syphilis, Tuberculosis, recurrent urogenital infections, prostatitis, and recurrent prostatovesiculitis.
  • Sexual Dysfunction - Premature ejaculation, anejaculation, infrequent sexual intercourse, and erectile dysfunction.
  • Malignancies - Sellar masses, pituitary macroadenomas, craniopharyngiomas, and surgical or radiation treatment to these conditions, testicular tumors, or adrenal tumors leading to an excess of androgens.
  • Medications or Drugs - Cannabinoids, opioids, psychotropic drugs 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.
  • Environmental toxins - Insecticides, fungicides, pesticides, smoking, excess alcohol.

Male infertility can also be classified based upon the medical interventions that can potentially assist conception.[7]

  • Untreatable male sterility is seen in 12% - Primary seminiferous tubular failure, Sertoli cell-only syndrome, bilateral orchiectomy.
  • Treatable causes of male infertility are found in 18% - Obstructive azoospermia, ejaculatory duct, and prostatic midline cysts, gonadotropin deficiency, sexual function disorders, sperm autoimmunity, varicoceles, and reversible toxin effects.
  • Untreatable male infertility is found in 70% - Oligozoospermia, asthenozoospermia, teratozoospermia, and normospermia with functional defects. Assisted reproductive techniques will be necessary for reproduction.

Epidemiology

The prevalence of infertility is variable and epidemiologically, male infertility has been documented less in developing countries.[8] The burden of infertility is generally worse in the developing world due to the constrained medical resources and the high cost of treatment as well as cultural fears, taboos, and stigmas.  It is much more difficult to identify and manage infertility where medical resources are already strained with basic health care.

Globally, infertility affects approximately 13% to 15% of all couples while one in five is unable to achieve pregnancy in the first year.[9] About 50% of young, healthy couples in the US who could not create a pregnancy during their first year of unprotected sexual intercourse, will successfully conceive during the subsequent twelve months even without any specific treatment.[10]  With the first child, one in six couples encounter some fertility problems and with a subsequent child, one in six still has issues.[11] In 20% to 30% of infertility cases, males can be solely responsible with an overall contribution to infertility in couples of about 50%.[12]

With regard to male infertility, the exact prevalence is still doubtful as male infertility is not a reportable disease. Furthermore, payment for male infertility treatment is usually private and hence they 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.[6] 

Agarwal et al estimated the overall pure male factor infertility could range between 2.5% and 12%.[12]  In North America, the estimated male infertility rate is between 4.5% - 6% while its 9% in Australia and could be as high as 8% to 12% in Eastern Europe.[12] A study by Bayasgalan et al estimated the cause of infertility due exclusively to a male factor at 25.6%.[13] In a study conducted by Thonneau et al among the French population, a prevalence of 20% infertility due just to a male factor was found.[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%.[14][15] For most practical purposes, we assume that about one sixth of all couples worldwide have an issue with infertility and that the male factor is significant in about half and is the only cause in about 20% to 30%.

Of greater concern is the widely reported general trending, over recent decades, of reductions in sperm counts globally.[16] The average sperm counts in 1940 were 113 million/mL but dropped to 66 million/mL in the 1990s.[17] 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. 

Infertile men appear to have an increased risk of developing cancer compared to the general population.  This risk is highest in azoospermic men.[18] For example, it has been reported that 5% to 8% of patients with testicular cancer have azoospermia.[19]

Pathophysiology

Male infertility can also be classified as: 

Pre-testicular causes would include hypogonadotropic hypogonadism, erectile dysfunction, or coital disorders such as retrograde ejaculation, anejaculation, genetic factors, chromosomal abnormalities.

Testicular disorders would cover 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.[20][21]

Post-testicular etiologies would include lesions of the seminal tract, inflammatory diseases, congenital absence of the vas deferens, post-vasectomy, erectile dysfunction, premature ejaculation, and 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 normal men, 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) as well as 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 prior to age one. Starting even before one 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.[22][23][24]

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.[25][26]

Klinefelter's: 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 common diagnosed cause of primary hypogonadism even though the majority of men with Klinefelter's (50% to 75%) are never diagnosed at all.  The incidence is approximately 1 to 2 per 1,000 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 which is possible in about 20% of Klinefelter's patients who may demonstrate some normal spermatocytes and spermatids.[27]  Aside from fertility concerns, the usual treatment of Klinefelter's in adults is with full testosterone replacement therapy.[28][29][30][31]

Prolactinoma: Prolactin levels in men are normally 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 above 150 mcg/L are suggestive of this condition while a level above 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 therapy with a trans-sphenoidal resection of the prolactinoma is successful in 80 - 90% of cases, but the tumors often recur.  Surgery is usually reserved for patients with visual field loss and in those where medical therapy is unsuccessful or not well tolerated.[32]  

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. Testicular atrophy may occur from 1 to 6 months after the infection. 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.[33][34]

History and Physical

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

  1. to determine if the male factor is contributing to the infertility issue
  2. to identify the small percentage of cases (about 20%) that can be normalized with treatment
  3. to determine if assisted reproductive techniques (ART) would ultimately benefit the couple 

The evaluation starts with a complete and comprehensive sexual and medical history including reproductive history, family history, 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, STDs, tuberculosis, mumps, scrotal infections such as epididymitis, prior biological children produced, maternal exposure to DES, anosmia (associated with Kallman syndrome), breast enlargement and galactorrhea, precocious puberty (at 9 years of age or earlier), etc. An undescended testicle, whether unilateral or bilateral, can have an effect on 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 STDs (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 KY jelly, saliva, and others) should be eliminated. Non-toxic lubricants would include egg whites, peanut 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 an endocrinopathy, gynecomastia, skin, hair distribution, and particularly the secondary sexual characteristics. If the patient appears muscular and has a low sperm count, do an endocrine screening panel as he could have a very low LH which would be suggestive of testosterone abuse. Obesity tends to increase the peripheral conversion of testosterone to estrogen.  This decreases LH levels and has been associated with reduced sperm counts. 

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

Testicular size should be measured.  In a normal 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 less than 4 cm in its largest dimension, it is considered "small". The presence or absence of the vas deferens should be noted and documented. The 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 in the absence of any clinical signs of cystic fibrosis.[35]  Any clinical abnormalities of the testicles should be identified such as epididymal lesions, spermatoceles, and large varicoceles.

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

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 regards 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%.[36] Only clinically significant varicoceles are generally believed to have an impact on male fertility but this is somewhat controversial.[37][38][39][40] When present, varicoceles are typically found on the left side due to anatomical reasons. Isolated right-sided varicoceles are suggestive of retroperitoneal pathology such as renal cell carcinoma with an obstructing tumor thrombus in the vena cava.

Bilateral absence of the vas deferens on physical examination is associated with CFTR gene mutations and both partners should be genetically checked. If a positive result is found, genetic counseling should be done prior to any assisted reproductive techniques, 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 and thin skin with multiple bruises and stretch marks would be suggestive of Cushing disease while patchy, diffuse hyperpigmentation might suggest iron overload syndrome. 

In general, if a patient has azotemia 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 two separate samples should be collected, separated by at least one week. At least 3 days of abstinence should precede the first specimen.[41] This is recommended due to the extremely high degree of variability in semen analyses.[42]  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.[43][44] Semen analyses greatly assist in identifying and classifying the severity of any male factor.

A detailed methodology of collecting the semen has been published by the World Health Organization (WHO). 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 important 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.[45] 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 an hour of collection.

The standards of 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.[46]

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

The Lower Reference Limits of a Semen Analysis (with 95th percent confidence intervals) Adapted from WHO (2010):[47]  

pH > 7.2

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.)

Sperm concentration: 15 million per mL (12 – 16) [Usual normal value is > 20 million per mL.] If low, check for varicocele and consider a hormonal analysis.

Total sperm count: 39 million per ejaculate (33 – 46)

Sperm Morphology (normal) forms: > 4% [Usual normal value > 30%]

Motility: 40% (38 – 42) [Usual normal value is 60%](If low, check for varicocele and consider antisperm antibodies test.)

Vitality: 58% live (55 – 63) If low, check for varicocele and consider antisperm antibodies test.

Progressive motility: 32% (31 – 34%)

Total motility: > 40% [Usual normal value is > 60%] If low, check for varicocele and consider antisperm antibodies test.

Forward progression > 2 

Seminal Fructose > 13 Micormol/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 mcmol/ejaculate
  • Seminal neutral glucosidase = <20 milliunits /ejaculate
  • Seminal zinc = >2.4 mcmol/ejaculate

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)[48]

Aspermia - No ejaculate at all.

Asthenozoospermia <32% progressively motile spermatozoa. Absolute asthenozoospermia is when no sperm moves at all but they are not dead.

Azoospermia - No spermatozoa in the ejaculate.

Cryptozoospermia - Spermatozoa absent from fresh preparation but observed in a centrifuged pellet.

Leukospermia -  >1 × 10 ml leucocytes in the 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 × 10/ml; total sperm number <39 × 10/ml.

Oligo-astheno-teratozoospermia - Disturbance of all three parameters.

Teratozoospermia - <4% morphologically normal spermatozoa.

Other tests include: 

Antisperm Antibodies (ASA): should be suspected with sperm agglutination or isolated asthenozoospermia with normal 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.[49]

Genetic Screening: and chromosomal testing may be indicated with azoospermia or severe oligozoospermia as chromosomal defects are more common in infertile men (up to 15%) than in normal males (about 0.6%).[50] 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 (CTFR) 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. Endocrine (hormonal) lab test panel would include serum follicle-stimulating hormone (FSH), testosterone, luteinizing hormone (LH), prolactin, thyroid-stimulating hormone (THS, optional), and estradiol (optional) 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, free testosterone, and estradiol.

  • 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 high FSH is 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 checked for CTFR gene mutations. 
  • High testosterone and LH but normal FSH: This would be consistent with partial androgen resistance.
  • Cushing 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.

Post-coital 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 post-coital test. The test is done by examining the cervical mucus for viable sperm 8 hours after intercourse.  It is optimally done 1-2 days prior to 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 post-coital 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 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 be used to 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 below 1.0 ml, as a post-ejaculatory analysis for sperm may be required to confirm retrograde ejaculation.[51]  Note: such sperm collected can be used for IVF with ICSI.

Scrotal Ultrasound: would be 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. Non-palpable varicoceles found only on scrotal ultrasound are generally not considered clinically significant and varicocelectomy is not usually recommended to improve fertility by most experts but this is somewhat controversial. 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.[52] Routine use of scrotal ultrasound in male infertility is controversial, but 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.  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.[53]

Testicular biopsy: may be indicated in some cases to exclude spermatogenic failure. Testicular biopsy is typically done 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 doing the biopsy but care must be used to avoid killing the sperm with preservatives. There is a reported discrepancy in findings on testicular biopsy between the two sides, so consider bilateral biopsies.

Transrectal ultrasound (TRUS): can identify ejaculatory duct obstruction where dilated ejaculatory ducts and seminal vesicles are seen.[54]  It should be considered, along with post-ejaculatory urinalysis, when semen volume is low. 

Vasography: 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 one 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.  In vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), an advanced form of assisted reproduction should be considered in these cases.

Low motility (asthenozoospermia): Check for anti-sperm antibodies for severe, isolated asthenozoospermia (low motility), especially if associated with increased agglutination. Treatment includes the use of condoms to minimize exposure, immunosuppressive steroid therapy for both partners, special processing of sperm for direct intrauterine insemination, and in vitro fertilization (IVF).  Low motility is often due to disorders or pathology of the epididymides or a structural defect of the sperm's flagellum.[55][56]

Low morphology (teratozoospermia): Not to be confused with leukocytes, large numbers of immature germ cells in the semen suggests an issue with spermatogenesis.  Treatment would be ART, possible 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 by itself does not appear to affect natural pregnancy rates unless it is quite severe.[57]  In such cases, artificial reproductive techniques (ART) like intracytoplasmic sperm injection (ICSI) can be used to treat the infertility.

Low sperm count or concentration (oligozoospermia)(<10 million/ml) : Check hormone levels (testosterone, FSH, LH, and prolactin). 

Low testosterone with high FSH and LH: suggests possible Klinefelter's. Karyotyping is recommended as Klinefelter's is likely, especially if their testes are small and firm bilaterally. If the karyotyping is normal, consider assisted reproductive techniques, possible IVF with ICSI. If severe oligoozoopermia (less than 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.[58] Such genetic problems can be transmitted to the offspring by ART and IVF with ICSI. Other causes include post cancer chemo and radiation therapy, bilateral testicular trauma or torsions and significant testicular infections such as mumps.[59][60]

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 testis size: evaluate for genital tract obstruction: (especially if poor sperm motility is also present)[61]

  • Congenital absence of the vas deferens can be detected on physical examination. May be associated with abnormally low semen pH. Can be verified with scrotal or transrectal ultrasound.[62][63]
  • May also be associated with cystic fibrosis mutations and a solitary kidney. Genetic testing and renal ultrasonography can be diagnostic and confirmatory.[62][63]
  • Ejaculatory duct obstruction can also be caused by STD infections or post-vasectomy. Scrotal ultrasound would typically showed dilated seminal vesicles secondary to infections like chlamydia, gonorrhea, tuberculosis, or surgical vasectomy. Scrotal or transrectal ultrasound in such cases shows dilated seminal vesicles.[64]

High testostereone with a high LH and normal FSH: suspicious for partial or total androgen resistance. May also have gynecomastia with a variable presentation of male genitalia.[65]

Any testosterone level with a low LH in an athletic or very muscular male: consider possible androgen abuse.[66]

Low sperm count, low motility, and low morphology (oligo-astheno-teratozoospermia): When mild, this could indicate a "stress pattern" that might respond well to a varicocelectomy if one is present.  When severe, infertility is highly likely.  Treatment would be ART, possible IVF with ICSI.[57] 

Very low sperm count (severe oligozoospermia) or no sperm (azoospermia): Check hormone levels and consider genetic testing. If vas are present on physical examination and testicular volumes are normal, possible obstructive azoospermia. Obstructive azoospermia can usually be treated surgically with vasovasostomy or vasoepididymostomy but even if the surgery fails, the condition can always be treated with ART as viable sperm is available directly from the testicle via biopsy. 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.  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.[67] Chromosomal testing should be done in these men but NOT if they have a sperm concentration greater than 5 million/ml as chromosomal microdeletions would be quite rare.[68] Microdeletions of the Y chromosome is one of the genetic disorders that can be transmitted to male children via ICSI.[69]

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 post-ejaculation 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.[70]

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 azoopsermia or an extremely low sperm count might be due to ejaculatory duct obstruction or from congenital bilateral absence of the vas deferens where there is a failure of seminal vesicle development.[71]

White blood cells in the semen (pyospermia or leukospermia): Leukocytes are normally found in the semen. Levels above 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 therefore very tempting to attempt to treat leukospermia with antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs), but 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 antibiotic or other treatment in controlled trials.[11][72][73]

Treatment / Management

No Treatment: When left untreated, some infertile couples still manage to produce 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 two years.[74] 

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.[75][76][77][78] Low body weight is also a possible risk factor for male infertility.[79] Fish oil supplements have also been suggested as helpful in male fertility but there is insufficient evidence to make a recommendation. [79]

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.[80] While avoiding hot baths, saunas and tight-fitting underwear has not been conclusively demonstrated to significantly improve male fertility, 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.[76]

"Empirical, Optional and Controversial" Therapies: Clomiphene, Tamoxifen, Aromatase Inhibitors, Carnitine, and Antioxidants:

It is often difficult for physicians to suggest or even discuss non-traditional, 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 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 infertility treatment. The therapies are relatively inexpensive and using them may provide some psychological benefit. There are enough reports of a potential benefit to justify a clinical trial in infertility patients who cannot afford or are not otherwise candidates for other treatments.[81][82] It also gives the physician a way to provide a "treatment" while actually just giving the couple more time for natural conception. 

Clomiphene is an anti-estrogen and in small doses (25 to 50 mg 3 times per week) can increase gonadotropins (FSH and LH) and stimulate spermatogenesis making it potentially useful in idiopathic cases of male infertility. Most patients will notice an improvement in semen analyses in three months, but some will need 6 weeks or longer.[83]  This benefit can be increased by adding tamoxifen (10 mg twice daily) which also acts as an estrogen receptor antagonist.[81][84][85] Clomiphene is also possibly helpful in hypogonadotropic hypogonadism although there is limited data showing any significant improvement in pregnancy rates.[82][86]

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.[87] A recent review and meta-analysis of aromatase inhibitors for male infertility have suggested that these drugs are able to statistically improve abnormal semen and hormonal parameters plus they appear to be safe.[88] They are most useful when testosterone levels are normal but estradiols (estrogens) are relatively high. Also, they can be used together with clomiphene. Both the steroid-based (testolactone) and nonsteroidal (anastrozole and letrozole) drugs appear to have equivalent efficacy, but it is difficult to recommend any aromatase inhibitor without adequate, prospective, randomized placebo-controlled multicenter trials to definitively determine their efficacy and optimal dosage.[87][88][89] Anastrozole and letrozole are inexpensive with minimal side effects. The recommended dose of Anastrozole for male infertility is 1 mg three times a week while the dose for letrozole would be 2.5 mg also three times weekly. The most common side effect of these medications is joint pain and stiffness. 

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, non-toxic general therapy for male infertility.[90] It is known to increase fatty acid transport into sperm mitochondria which are needed for epididymal sperm energy production. It also appears to increase sperm motility, morphology, and maturation while reducing apoptosis.[91] 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 although motility was not affected and the study was of insufficient duration to determine if pregnancy rates were affected.[92][93] A daily dose of 3 grams per day has been suggested.

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. A three year, a multi-institutional study from nine fertility centers that included 174 infertile male patients using anti-oxidant therapy alone, without L-carnitine, showed no benefit in improving semen parameters or pregnancies for the 6 months the patients were followed.[94] However, there are significant other data to support antioxidant use for male infertility.[95][78][96][97] The most studied vitamins, minerals, and antioxidants include coenzyme Q10, vitamin C, vitamin E, folic acid, selenium, and zinc.[98] 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 (12 mg), folic acid (400 micrograms) and selenium (200 mg every other day) taken for three months resulted in statistically significant improvements in sperm count, concentration, motility, progressive motility, and morphology as well as better semen volume and pH.[99] 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 the coenzyme Q10 was discontinued. Pregnancy rates were not reported.[100]  While there is insufficient data to formally recommend antioxidant therapy for mild to moderate male factor infertility, a clinical trial may not be unreasonable in selected couples. Further studies are needed to definitively determine the value of antioxidant therapy as well as the optimal ingredients and dosages. 

Overall, there is certainly a paucity of data to definitively support recommending any of these therapies, but it may not be unreasonable to offer one or more of them to a couple for consideration. Every practitioner will need to decide for themselves whether or not to offer any of these tempting but still 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.[90][94][101][102][103][104] 

Gonadotropic Therapy

The use of gonadotropin therapy in most men with idiopathic infertility is controversial. A meta-analysis of six randomized trials of gonadotropic therapy in male infertility patients reported higher pregnancy rates than the placebo group but the overall quality of these studies was low with highly variable treatment protocols and follow-up periods.[105] 

We know that 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.[106] 

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. Human menopausal gonadotropin (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.)[107][108][109][110]

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 to be effective in normalizing fertility.[111] In one study, combination therapy with HCG and FSH for a period of one to two years increased testicular size in almost every patient, improved spermatogenesis in about 80% of men, and increased pregnancy rates to about 50%.[110][112][113]

Sexual Disorders

Sexual intercourse during the most fertile period should be at least twice a week. Erectile dysfunction should be treated. Retrograde ejaculation can be treated with oral sympathomimetic drugs although there is little data on its ultimate effectiveness in producing pregnancy in a couple with infertility.[114][115] 

Ejaculatory Duct Cyst Puncture or Resection

Midline prostatic and ejaculatory duct cysts are present in about 10.2% of all infertile men. 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 on transrectal ultrasound examinations.[116][117] To be clinically significant, it's been suggested that the cysts need to be >0.017 mL in size. They are identified from a transrectal ultrasound. The cysts can be treated either with transurethral resection or by cyst puncture with aspiration with transrectal ultrasound.[118] 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.[116][117][119]

Varicocelectomy

Varicocele repairs are generally only recommended in infertile men with abnormal semen parameters who have large, clinical grade 3 varicoceles.  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, 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.[40][120][121] Overall, varicocelectomy is expected to ultimately improve semen parameters in about 60% to 70% of patients. While there is data to support an improved pregnancy rate in men after varicocele surgery, the evidence is somewhat conflicting.[37][122]  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 these men will see any improvement in their fertility potential. 

Recent studies have suggested that subclinical varicoceles may sometimes have an impact on semen characteristics based on testicular size and intratesticular hemodynamics rather than varicocele size, palpability, or vein diameter. 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.[92][120][123][124] A high resistive index along with 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, it's possible that 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 along with an honest and comprehensive discussion of the pros and cons of surgery with the patient and family is still the best advice on helping men 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 be helpful in performing 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 greatly 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.[125] Men with increased FSH levels may require additional assisted reproductive treatment to achieve a pregnancy even after successful surgery.[126] Varicocele repairs and vasovasostomies should never be done at the same time 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%.[127][128]

Intrauterine Insemination (IUI)

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 where the postcoital test showed 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, but when combined with female superovulation the success rate increases up to 17% per attempt. The overall rate is about 12% per attempt but the rate goes down as more attempts are made.  Pregnancy rates increase to about 40-50% after 9 attempts. 

Intrauterine insemination techniques should not be used when the sperm are dead (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. 

In general, 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).

While less reliable than ICSI outlined below, it 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 is not too inadequate. 

In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI)

IVF can be used in couples where intrauterine insemination has failed and where there are known conditions precluding the use of simpler techniques. IVF involves the fertilization of the female egg outside of her body.  About 100,000 sperm are added for each egg in a special medium. A minimum of 50,000 to 500,000 motile sperm are generally required for IVF; otherwise, ICSI will be required. 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 four embryos are implanted into the female partner and the remaining embryos are frozen. Pregnancy rates are reported at 10% to 45%.

The ultimate assisted reproductive technique 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.[129]  This rate increases by up to 45% for multiple cycles.[129] Multiple fetuses occur in about 30% to 40% of all pregnancies produced by IVF with ICSI. 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 contraindication to the procedure is 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. A list of some of the more common causes follows:

  • Adult growth hormone deficiency 
  • 5-Alpha reductase deficiency
  • Androgen receptor gene polymorphisms
  • Brain damage from tumors or trauma
  • Bilateral testicular torsion
  • 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 
  • Hodgkin lymphoma (due to need for extensive chemotherapy)
  • HIV infections (causes low sperm motility) 
  • Human beta-defensin abnormalities
  • Hypogonadotropic hypogonadism
  • Hypogonadism
  • Hypopituitarism 
  • Immotile cilia syndrome
  • Kallmann syndrome
  • Kartagener syndrome
  • Klinefelter's 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  
  • Renal failure
  • Reifenstien syndrome (partial androgen insensitivity)
  • Sarcoidosis
  • Seminomatous and non-seminomatous germ cell testicular tumors 
  • Sex reversal syndrome
  • 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
  • STDs
  • Testicular cancers 
  • Testicular trauma
  • Testosterone supplementation
  • Thalassemia
  • Tuberculosis
  • Thyroid disorders
  • Torsion of the testicles
  • Tuberculosis 
  • Urethral infection, stricture or trauma 
  • Varicoceles
  • Young syndrome

Prognosis

The prognosis of the male infertility is individualized and depends upon the cause. An appropriate workup should be done based on need and necessity. Such investigations have to happen after a frank and honest discussion with the patient, as it has both financial and psychological implications. Following an appropriate workup, reasonable selected treatments, counseling, surgery or ART can be offered to the couple.

Complications

Complications are typically due to psychological distress, stress, and issues with the marital relationship. 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 of the surgical procedures.

Consultations

Physicians dealing with infertility couples should be prepared to refer patients for genetic counseling, reproductive endocrinology, and assisted reproductive services such as intrauterine insemination, in vitro fertilization 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 which can be quite severe in some cultures.  

Counseling may be needed for some couples, as infertility is associated with psychological distress. This is particularly important if genetic abnormalities are found.

Deterrence and Patient Education

Healthy lifestyle changes and practices are generally helpful in improving fertility. Patients are encouranged to stop smoking, eliminate cannabis use, reduce weight, and stop drinking excess alcohol as these healthy lifestyle changes may help.

Pearls and Other Issues

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

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

A minimum of two semen analyses is recommended before making any conclusions regarding male infertility.

It is imperative that both partners be examined to properly identify all the causes and contributing factors of their infertility. 

Men with normal hormonal levels (or isolated FSH elevation) together with very low sperm concentrations (less than 5 million/mL) should be checked for Y chromosomal defects.

Bilateral absence of the vas on clinical examination suggests a cystic fibrosis transmembrane conductance regulator (CTFR) gene mutation; especially if associated with a positive family history.

Normal-sized testicles with low semen volumes suggest retrograde ejaculation or ejaculatory duct obstruction. Get a transrectal ultrasound and check a post-ejaculatory urinalysis.

Suspect testosterone abuse in muscular men with small testes.

Azoospermia with bilateral atrophic testes is exceedingly difficult to treat without ART.  Possible Klinefelter's if associated with hypogonadism.

Vitamin D supplementation may help with sperm motility.[130]

It may not be unreasonable to suggest that a couple with a male infertility factor consider a trial of treatment with one of the "unproven" therapies if no better treatment alternative is immediately available. This will buy time and there is very little harm done even if they don't work. A pregnancy may develop just from waiting. Some of the treatments for them to consider would include clomiphene (with or without tamoxifen), aromatase inhibitors, and antioxidants (including coenzyme Q10 and L-carnitine). The treatments should be presented as possible fertility aides for which there may be some evidence of efficacy. The couple should be informed of the available data and allowed to decide for themselves. They should not have unrealistic expectations about the efficacy of any of these remedies. 

Know who to refer infertile couples to in your community for reproductive endocrinology assistance as well as ART and IVF with ICSI.  It is helpful to know the cost of these services in your community so patients can be informed. 

Do not be afraid to discuss adoption as a reasonable alternative to expensive fertility treatments.

Summary of the 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. For example, varicoceles can be surgically corrected while bilateral small, firm testes would suggest Klinefelters and bilateral absence of the vas deferens is associated with cystic fibrosis.

At least two, separate semen analyses are required.

Hormonal screening should be performed which should include testosterone, FSH, LH, and prolactin. A TSH level and estradiol can optionally 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 obvious cause, consider discussing some of the optional treatments as noted earlier. 

We have prepared a patient handout (below) to help couples determine if they wish to pursue any of the optional treatments discussed. 

A Couple’s Guide to Optional Treatments for Male Infertility

Few patients are as anxious or desperate as the couple who have failed to conceive a child. It takes at least one 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 two years without ever getting any treatment at all.

The purpose of this guide is to inform couples about some of the somewhat unorthodox or unofficial 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. This guide is not intended as a substitute for your physician’s advice and you should always check with your doctor before starting any new treatment.

Standard lifestyle improvements, such as a healthy diet, losing weight, and exercising as well as 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.)

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

Those with relatively mild sperm defects might possibly benefit from trying one or more of the various 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 of the remedies will require at least three months of continuous treatment to show any benefit, and several will need six months.

Clomiphene

Clomiphene is an anti-estrogen drug that is primarily used as a fertility-enhancing drug for women. Men make a very small amount of estrogen and there is evidence that, in low doses, clomiphene can increase male fertility hormones (FSH and LH) and stimulate sperm production by lowering their estrogen levels. It may also be useful in some hypogonadal, infertile men with low testosterone levels. The recommended dose is 25mg or 50 mg three times per week. The estimated cost is about $20 per month. A prescription will be required.

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 officially recommend it. The usual dose is 10 mg twice a day.

Aromatase Inhibitors (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 three times a week while the dose of letrozole is 2.5 mg three times a week. The estimated monthly cost for either of these drugs is about $10. The most common side effect reported with these medications is joint pain and stiffness. A prescription is required.

Antioxidants, Vitamins, and Minerals

The most studied vitamins, minerals, and antioxidants for male infertility include 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 dosages. Given their low cost and lack of any negative effects, they should probably be part of the treatment regimen for every male infertility patient. Monthly cost varies but is generally nominal. Some combination products promoted specifically for male infertility may be more costly and therefore are not recommended. No prescription is needed.

L-Carnitine

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, non-toxic general therapy for male infertility. It increases sperm motility and maturity. A six-month trial is suggested using a daily dose of 3 grams per day. Since it is an amino acid, its use is extremely safe. No prescription is required.

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

  • L-Carnitine: 3 grams daily.
  • Coenzyme Q10: 300 mg daily.
  • Folic acid: 1000 mg daily
  • Selenium: 200 mg daily.
  • Vitamin C: 500 mg twice a day.
  • Vitamin D: 5,000 units daily.
  • Vitamin E: 400 units daily.
  • Zinc: 40 mg daily.

Anti-Estrogen Medications

  • Clomiphene: 25 – 50 mg three times a week, plus either:
  • Anastrozole: 1 mg three times a week, or
  • Letrozole: 2.5 mg three times a week, or
  • Tamoxifen: 10 mg twice a day

Enhancing Healthcare Team Outcomes

The care coordination should be between family physician, urologist, endocrinologist, and an andrologist who are experienced in diagnosing and managing male infertility. It is recommended that primary care 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 found in the clinical or genetic investigation or those who carry a (potential) 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 as well as their families.  The barriers from stigmas associated with infertility arising due to religious and cultural beliefs should be considered and reduced where possible.


References

[1] Definitions of infertility and recurrent pregnancy loss. Fertility and sterility. 2008 Nov;     [PubMed PMID: 19007647]
[2] Thonneau P,Marchand S,Tallec A,Ferial ML,Ducot B,Lansac J,Lopes P,Tabaste JM,Spira A, Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989). Human reproduction (Oxford, England). 1991 Jul;     [PubMed PMID: 1757519]
[3] Hull MG,Glazener CM,Kelly NJ,Conway DI,Foster PA,Hinton RA,Coulson C,Lambert PA,Watt EM,Desai KM, Population study of causes, treatment, and outcome of infertility. British medical journal (Clinical research ed.). 1985 Dec 14;     [PubMed PMID: 3935248]
[4] Shih KW,Shen PY,Wu CC,Kang YN, Testicular versus percutaneous epididymal sperm aspiration for patients with obstructive azoospermia: a systematic review and meta-analysis. Translational andrology and urology. 2019 Dec;     [PubMed PMID: 32038959]
[5] Honig SC,Lipshultz LI,Jarow J, Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertility and sterility. 1994 Nov;     [PubMed PMID: 7926114]
[6] Winters BR,Walsh TJ, The epidemiology of male infertility. The Urologic clinics of North America. 2014 Feb;     [PubMed PMID: 24286777]
[7] Barak S,Baker HWG, Clinical Management of Male Infertility 2000;     [PubMed PMID: 25905383]
[8] Cates W,Farley TM,Rowe PJ, Worldwide patterns of infertility: is Africa different? Lancet (London, England). 1985 Sep 14;     [PubMed PMID: 2863605]
[9] Esteves SC,Miyaoka R,Agarwal A, An update on the clinical assessment of the infertile male. [corrected]. Clinics (Sao Paulo, Brazil). 2011;     [PubMed PMID: 21655766]
[10] Evers JL, Female subfertility. Lancet (London, England). 2002 Jul 13     [PubMed PMID: 12126838]
[11] Jungwirth A,Giwercman A,Tournaye H,Diemer T,Kopa Z,Dohle G,Krausz C, European Association of Urology guidelines on Male Infertility: the 2012 update. European urology. 2012 Aug;     [PubMed PMID: 22591628]
[12] Agarwal A,Mulgund A,Hamada A,Chyatte MR, A unique view on male infertility around the globe. Reproductive biology and endocrinology : RB     [PubMed PMID: 25928197]
[13] Bayasgalan G,Naranbat D,Tsedmaa B,Tsogmaa B,Sukhee D,Amarjargal O,Lhagvasuren T,Radnaabazar J,Rowe PJ, Clinical patterns and major causes of infertility in Mongolia. The journal of obstetrics and gynaecology research. 2004 Oct;     [PubMed PMID: 15327454]
[14] Philippov OS,Radionchenko AA,Bolotova VP,Voronovskaya NI,Potemkina TV, Estimation of the prevalence and causes of infertility in western Siberia. Bulletin of the World Health Organization. 1998;     [PubMed PMID: 9648359]
[15] Ikechebelu JI,Adinma JI,Orie EF,Ikegwuonu SO, High prevalence of male infertility in southeastern Nigeria. Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology. 2003 Nov;     [PubMed PMID: 14617473]
[16] Sengupta P,Dutta S,Krajewska-Kulak E, The Disappearing Sperms: Analysis of Reports Published Between 1980 and 2015. American journal of men's health. 2017 Jul     [PubMed PMID: 27099345]
[17] Carlsen E,Giwercman A,Keiding N,Skakkebaek NE, Evidence for decreasing quality of semen during past 50 years. BMJ (Clinical research ed.). 1992 Sep 12     [PubMed PMID: 1393072]
[18] Eisenberg ML,Betts P,Herder D,Lamb DJ,Lipshultz LI, Increased risk of cancer among azoospermic men. Fertility and sterility. 2013 Sep     [PubMed PMID: 23790640]
[19] Petersen PM,Skakkebaek NE,Vistisen K,Rørth M,Giwercman A, Semen quality and reproductive hormones before orchiectomy in men with testicular cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999 Mar     [PubMed PMID: 10071288]
[20] Stillman RJ, In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance and male and female offspring. American journal of obstetrics and gynecology. 1982 Apr 1     [PubMed PMID: 6121486]
[21] Hikim AP,Lue YH,Wang C,Reutrakul V,Sangsuwan R,Swerdloff RS, Posttesticular antifertility action of triptolide in the male rat: evidence for severe impairment of cauda epididymal sperm ultrastructure. Journal of andrology. 2000 May-Jun     [PubMed PMID: 10819451]
[22] Kogan SJ, Fertility in cryptorchidism. An overview in 1987. European journal of pediatrics. 1987     [PubMed PMID: 2891514]
[23] van Brakel J,Kranse R,de Muinck Keizer-Schrama SM,Hendriks AE,de Jong FH,Hack WW,van der Voort-Doedens LM,Bangma CH,Hazebroek FW,Dohle GR, Fertility potential in a cohort of 65 men with previously acquired undescended testes. Journal of pediatric surgery. 2014 Apr     [PubMed PMID: 24726121]
[24] Schneuer FJ,Milne E,Jamieson SE,Pereira G,Hansen M,Barker A,Holland AJA,Bower C,Nassar N, Association between male genital anomalies and adult male reproductive disorders: a population-based data linkage study spanning more than 40 years. The Lancet. Child & adolescent health. 2018 Oct     [PubMed PMID: 30236382]
[25] Hadziselimovic F,Hocht B,Herzog B,Buser MW, Infertility in cryptorchidism is linked to the stage of germ cell development at orchidopexy. Hormone research. 2007     [PubMed PMID: 17356291]
[26] Hadziselimovic F,Herzog B, The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet (London, England). 2001 Oct 6     [PubMed PMID: 11597673]
[27] Boeri L,Palmisano F,Preto M,Sibona M,Capogrosso P,Franceschelli A,Ruiz-Castañé E,Sarquella-Geli J,Bassas-Arnau L,Scroppo FI,Saccà A,Gentile G,Falcone M,Timpano M,Ceruti C,Gadda F,Trost L,Colombo F,Rolle L,Gontero P,Montorsi F,Sánchez-Curbelo J,Salonia A,Montanari E, Sperm retrieval rates in non-mosaic Klinefelter patients undergoing testicular sperm extraction: What expectations do we have in the real-life setting? Andrology. 2020 May     [PubMed PMID: 31999885]
[28] Gravholt CH,Chang S,Wallentin M,Fedder J,Moore P,Skakkebæk A, Klinefelter Syndrome: Integrating Genetics, Neuropsychology, and Endocrinology. Endocrine reviews. 2018 Aug 1     [PubMed PMID: 29438472]
[29] Groth KA,Skakkebæk A,Høst C,Gravholt CH,Bojesen A, Clinical review: Klinefelter syndrome--a clinical update. The Journal of clinical endocrinology and metabolism. 2013 Jan     [PubMed PMID: 23118429]
[30] Herlihy AS,Halliday JL,Cock ML,McLachlan RI, The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. The Medical journal of Australia. 2011 Jan 3     [PubMed PMID: 21449864]
[31] Berglund A,Viuff MH,Skakkebæk A,Chang S,Stochholm K,Gravholt CH, Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study. Orphanet journal of rare diseases. 2019 Jan 14     [PubMed PMID: 30642344]
[32] Kalsi AK,Halder A,Jain M,Chaturvedi PK,Sharma JB, Prevalence and reproductive manifestations of macroprolactinemia. Endocrine. 2019 Feb     [PubMed PMID: 30269265]
[33] Liu W,Han R,Wu H,Han D, Viral threat to male fertility. Andrologia. 2018 Dec     [PubMed PMID: 30569651]
[34] Davis NF,McGuire BB,Mahon JA,Smyth AE,O'Malley KJ,Fitzpatrick JM, The increasing incidence of mumps orchitis: a comprehensive review. BJU international. 2010 Apr     [PubMed PMID: 20070300]
[35] Patrizio P,Asch RH,Handelin B,Silber SJ, Aetiology of congenital absence of vas deferens: genetic study of three generations. Human reproduction (Oxford, England). 1993 Feb     [PubMed PMID: 8473422]
[36] The influence of varicocele on parameters of fertility in a large group of men presenting to infertility clinics. World Health Organization. Fertility and sterility. 1992 Jun;     [PubMed PMID: 1601152]
[37] Kim HJ,Seo JT,Kim KJ,Ahn H,Jeong JY,Kim JH,Song SH,Jung JH, Clinical significance of subclinical varicocelectomy in male infertility: systematic review and meta-analysis. Andrologia. 2016 Aug     [PubMed PMID: 26589369]
[38] Pierik FH,Vreeburg JT,Stijnen T,van Roijen JH,Dohle GR,Laméris JS,Timmers T,Weber RF, Improvement of sperm count and motility after ligation of varicoceles detected with colour Doppler ultrasonography. International journal of andrology. 1998 Oct     [PubMed PMID: 9805240]
[39] Thirumavalavan N,Scovell JM,Balasubramanian A,Kohn TP,Ji B,Hasan A,Pastuszak AW,Lipshultz LI, The Impact of Microsurgical Repair of Subclinical and Clinical Varicoceles on Total Motile Sperm Count: Is There a Difference? Urology. 2018 Oct     [PubMed PMID: 29981299]
[40] Kohn TP,Ohlander SJ,Jacob JS,Griffin TM,Lipshultz LI,Pastuszak AW, The Effect of Subclinical Varicocele on Pregnancy Rates and Semen Parameters: a Systematic Review and Meta-Analysis. Current urology reports. 2018 May 17     [PubMed PMID: 29774482]
[41] Lotti F,Maggi M, Ultrasound of the male genital tract in relation to male reproductive health. Human reproduction update. 2015 Jan-Feb;     [PubMed PMID: 25038770]
[42] Poland ML,Moghissi KS,Giblin PT,Ager JW,Olson JM, Variation of semen measures within normal men. Fertility and sterility. 1985 Sep     [PubMed PMID: 4029428]
[43] Snick HK,Snick TS,Evers JL,Collins JA, The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Human reproduction (Oxford, England). 1997 Jul;     [PubMed PMID: 9262301]
[44] Rowe T, Fertility and a woman's age. The Journal of reproductive medicine. 2006 Mar;     [PubMed PMID: 16674009]
[45] Jones DM,Kovacs GT,Harrison L,Jennings MG,Baker HW, Immobilization of sperm by condoms and their components. Clinical reproduction and fertility. 1986 Dec     [PubMed PMID: 2439182]
[46] Gottardo F,Kliesch S, [Semen analysis: spermiogram according to WHO 2010 criteria]. Der Urologe. Ausg. A. 2011 Jan     [PubMed PMID: 21161160]
[47] Cooper TG,Noonan E,von Eckardstein S,Auger J,Baker HW,Behre HM,Haugen TB,Kruger T,Wang C,Mbizvo MT,Vogelsong KM, World Health Organization reference values for human semen characteristics. Human reproduction update. 2010 May-Jun;     [PubMed PMID: 19934213]
[48] Krausz C, Male infertility: pathogenesis and clinical diagnosis. Best practice     [PubMed PMID: 21397198]
[49] Zini A,Boman JM,Belzile E,Ciampi A, Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Human reproduction (Oxford, England). 2008 Dec;     [PubMed PMID: 18757447]
[50] Rucker GB,Mielnik A,King P,Goldstein M,Schlegel PN, Preoperative screening for genetic abnormalities in men with nonobstructive azoospermia before testicular sperm extraction. The Journal of urology. 1998 Dec     [PubMed PMID: 9817325]
[51] Sigman M,Boyle K,Jarow JP, Prevalence of sperm in the post-ejaculatory urine of fertile and subfertile men. Urology. 2008 Jan;     [PubMed PMID: 18242376]
[52] Pierik FH,Dohle GR,van Muiswinkel JM,Vreeburg JT,Weber RF, Is routine scrotal ultrasound advantageous in infertile men? The Journal of urology. 1999 Nov     [PubMed PMID: 10524881]
[53] Raman JD,Nobert CF,Goldstein M, Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. The Journal of urology. 2005 Nov     [PubMed PMID: 16217294]
[54] Jarow JP, Transrectal ultrasonography of infertile men. Fertility and sterility. 1993 Dec;     [PubMed PMID: 8243682]
[55]     [PubMed PMID: 3371483]
[56]     [PubMed PMID: 14640375]
[57] Wang C,Swerdloff RS, Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests. Fertility and sterility. 2014 Dec     [PubMed PMID: 25458617]
[58] Ferlin A,Arredi B,Speltra E,Cazzadore C,Selice R,Garolla A,Lenzi A,Foresta C, Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. The Journal of clinical endocrinology and metabolism. 2007 Mar     [PubMed PMID: 17213277]
[59]     [PubMed PMID: 20089613]
[60] Ross A,Bhasin S, Hypogonadism: Its Prevalence and Diagnosis. The Urologic clinics of North America. 2016 May     [PubMed PMID: 27132573]
[61]     [PubMed PMID: 25597249]
[62] Yu J,Chen Z,Ni Y,Li Z, CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis. Human reproduction (Oxford, England). 2012 Jan     [PubMed PMID: 22081250]
[63]     [PubMed PMID: 11119745]
[64]     [PubMed PMID: 8425637]
[65] Rosa S,Biason-Lauber A,Mongan NP,Navratil F,Schoenle EJ, Complete androgen insensitivity syndrome caused by a novel mutation in the ligand-binding domain of the androgen receptor: functional characterization. The Journal of clinical endocrinology and metabolism. 2002 Sep     [PubMed PMID: 12213902]
[66]     [PubMed PMID: 26855782]
[67] Fisch H,Braun SR, Trends in global semen parameter values. Asian journal of andrology. 2013 Mar     [PubMed PMID: 23291862]
[68] Grigorova M,Punab M,Poolamets O,Kelgo P,Ausmees K,Korrovits P,Vihljajev V,Laan M, Increased Prevalance of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men. The Journal of clinical endocrinology and metabolism. 2010 Jan     [PubMed PMID: 19897680]
[69] Grigorova M,Punab M,Ausmees K,Laan M, FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men. Human reproduction (Oxford, England). 2008 Sep     [PubMed PMID: 18567894]
[70] Perera ND,Hill JT, Erectile and ejaculatory failure after transurethral prostatectomy. The Ceylon medical journal. 1998 Jun     [PubMed PMID: 9704545]
[71] Weiske WH,Sälzler N,Schroeder-Printzen I,Weidner W, Clinical findings in congenital absence of the vasa deferentia. Andrologia. 2000 Jan     [PubMed PMID: 10702861]
[72] Schuppe HC,Pilatz A,Hossain H,Diemer T,Wagenlehner F,Weidner W, Urogenital Infection as a Risk Factor for Male Infertility. Deutsches Arzteblatt international. 2017 May 12     [PubMed PMID: 28597829]
[73] Hamada A,Agarwal A,Sharma R,French DB,Ragheb A,Sabanegh ES Jr, Empirical treatment of low-level leukocytospermia with doxycycline in male infertility patients. Urology. 2011 Dec     [PubMed PMID: 22137697]
[74] Matorras R,Diez J,Corcóstegui B,Gutiérrez de Terán G,García JM,Pijoan JI,Rodríguez-Escudero FJ, Spontaneous pregnancy in couples waiting for artificial insemination donor because of severe male infertility. European journal of obstetrics, gynecology, and reproductive biology. 1996 Dec 27     [PubMed PMID: 9119099]
[75]     [PubMed PMID: 30196946]
[76]     [PubMed PMID: 23870423]
[77] Jung A,Schuppe HC, Influence of genital heat stress on semen quality in humans. Andrologia. 2007 Dec     [PubMed PMID: 18076419]
[78] Benatta M,Kettache R,Buchholz N,Trinchieri A, The impact of nutrition and lifestyle on male fertility. Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2020 Jun 24     [PubMed PMID: 32597116]
[79]     [PubMed PMID: 19261274]
[80] Jung A,Leonhardt F,Schill WB,Schuppe HC, Influence of the type of undertrousers and physical activity on scrotal temperature. Human reproduction (Oxford, England). 2005 Apr     [PubMed PMID: 15618251]
[81] Chua ME,Escusa KG,Luna S,Tapia LC,Dofitas B,Morales M, Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis. Andrology. 2013 Sep     [PubMed PMID: 23970453]
[82] Whitten SJ,Nangia AK,Kolettis PN, Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertility and sterility. 2006 Dec     [PubMed PMID: 17007848]
[83] Ross LS,Kandel GL,Prinz LM,Auletta F, Clomiphene treatment of the idiopathic hypofertile male: high-dose, alternate-day therapy. Fertility and sterility. 1980 Jun     [PubMed PMID: 6769716]
[84] Kotoulas IG,Cardamakis E,Michopoulos J,Mitropoulos D,Dounis A, Tamoxifen treatment in male infertility. I. Effect on spermatozoa. Fertility and sterility. 1994 May     [PubMed PMID: 8174730]
[85] Paffenholz P,Votteler S,Nazari S,Nestler T,Salem J,Grabbert M,von Brandenstein M,Loosen SH,Zey S,Heidenreich A,Herden J,Denil J, Efficacy of the Oestrogen Antagonist Tamoxifen on Sperm Parameters in Patients with Idiopathic Oligoathenoteratozoospermia. Urologia internationalis. 2019     [PubMed PMID: 31067562]
[86] Willets AE,Corbo JM,Brown JN, Clomiphene for the treatment of male infertility. Reproductive sciences (Thousand Oaks, Calif.). 2013 Jul     [PubMed PMID: 23202725]
[87] Schlegel PN, Aromatase inhibitors for male infertility. Fertility and sterility. 2012 Dec     [PubMed PMID: 23103016]
[88] Del Giudice F,Busetto GM,De Berardinis E,Sperduti I,Ferro M,Maggi M,Gross MS,Sciarra A,Eisenberg ML, A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility. Asian journal of andrology. 2020 Jul-Aug     [PubMed PMID: 31621654]
[89] Pavlovich CP,King P,Goldstein M,Schlegel PN, Evidence of a treatable endocrinopathy in infertile men. The Journal of urology. 2001 Mar     [PubMed PMID: 11176482]
[90] Kopets R,Kuibida I,Chernyavska I,Cherepanyn V,Mazo R,Fedevych V,Gerasymov S, Dietary supplementation with a novel l-carnitine multi-micronutrient in idiopathic male subfertility involving oligo-, astheno-, teratozoospermia: A randomized clinical study. Andrology. 2020 Sep     [PubMed PMID: 32330373]
[91] Agarwal A,Said TM, Carnitines and male infertility. Reproductive biomedicine online. 2004 Apr     [PubMed PMID: 15149558]
[92] Tsampoukas G,Dellis A,Papatsoris A, Bilateral disease and intratesticular haemodynamics as markers of dyspermia in patients with subclinical varicocele: A prospective study. Arab journal of urology. 2019     [PubMed PMID: 31723447]
[93] Nazari L,Salehpour S,Hosseini S,Allameh F,Jahanmardi F,Azizi E,Ghodssi-Ghassemabadi R,Hashemi T, Effect of antioxidant supplementation containing L-carnitine on semen parameters: a prospective interventional study. JBRA assisted reproduction. 2020 Jun 29     [PubMed PMID: 32598834]
[94] Steiner AZ,Hansen KR,Barnhart KT,Cedars MI,Legro RS,Diamond MP,Krawetz SA,Usadi R,Baker VL,Coward RM,Huang H,Wild R,Masson P,Smith JF,Santoro N,Eisenberg E,Zhang H, The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertility and sterility. 2020 Mar     [PubMed PMID: 32111479]
[95] Hajjar T,Soleymani F,Vatanchian M, Protective Effect of Vitamin C and Zinc as an Antioxidant Against Chemotherapy-Induced Male Reproductive Toxicity. Journal of medicine and life. 2020 Apr-Jun     [PubMed PMID: 32742504]
[96] Ali M,Martinez M,Parekh N, Are antioxidants a viable treatment option for male infertility? Andrologia. 2020 May 19     [PubMed PMID: 32427374]
[97] Alahmar AT,Sengupta P, Impact of Coenzyme Q10 and Selenium on Seminal Fluid Parameters and Antioxidant Status in Men with Idiopathic Infertility. Biological trace element research. 2020 Jun 22     [PubMed PMID: 32572802]
[98] Ring JD,Lwin AA,Köhler TS, Current medical management of endocrine-related male infertility. Asian journal of andrology. 2016 May-Jun     [PubMed PMID: 27098657]
[99] Sadaghiani S,Fallahi S,Heshmati H,Teshnizi SH,Chaijan HA,Ebrahimi FFA,Khorrami F,Poorrezaeian M,Alizadeh F, Effect of antioxidant supplements on sperm parameters in infertile male smokers: a single-blinded clinical trial. AIMS public health. 2020     [PubMed PMID: 32258192]
[100] Safarinejad MR,Safarinejad S,Shafiei N,Safarinejad S, Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double-blind, placebo controlled, randomized study. The Journal of urology. 2012 Aug     [PubMed PMID: 22704112]
[101] Skoracka K,Eder P,Łykowska-Szuber L,Dobrowolska A,Krela-Kaźmierczak I, Diet and Nutritional Factors in Male (In)fertility-Underestimated Factors. Journal of clinical medicine. 2020 May 9     [PubMed PMID: 32397485]
[102] García-Baquero R,Fernández-Ávila CM,Álvarez-Ossorio JL, Empiric therapy for idiopathic oligoasthenoteratozoospermia. Actas urologicas espanolas. 2020 Jun     [PubMed PMID: 32284159]
[103] Terai K,Horie S,Fukuhara S,Miyagawa Y,Kobayashi K,Tsujimura A, Combination therapy with antioxidants improves total motile sperm counts: A Preliminary Study. Reproductive medicine and biology. 2020 Jan     [PubMed PMID: 31956290]
[104] Ribas-Maynou J,Yeste M, Oxidative Stress in Male Infertility: Causes, Effects in Assisted Reproductive Techniques, and Protective Support of Antioxidants. Biology. 2020 Apr 10     [PubMed PMID: 32290152]
[105] Finkelstein JS,Yu EW,Burnett-Bowie SA, Gonadal steroids and body composition, strength, and sexual function in men. The New England journal of medicine. 2013 Dec 19     [PubMed PMID: 24350954]
[106] Santi D,Granata AR,Simoni M, FSH treatment of male idiopathic infertility improves pregnancy rate: a meta-analysis. Endocrine connections. 2015 Sep     [PubMed PMID: 26113521]
[107] An Q,Zhang K,Fu L,Guo Y,Zhang C,Ge Z,Ma J,Gu Y,Zuo L, The impact of exogenous testosterone supplementation on spermatogenesis in a rat model of oligoasthenospermia. International journal of clinical and experimental pathology. 2020     [PubMed PMID: 32661465]
[108] Ramasamy R,Armstrong JM,Lipshultz LI, Preserving fertility in the hypogonadal patient: an update. Asian journal of andrology. 2015 Mar-Apr     [PubMed PMID: 25337850]
[109] Kovac JR,Scovell J,Ramasamy R,Rajanahally S,Coward RM,Smith RP,Lipshultz LI, Men regret anabolic steroid use due to a lack of comprehension regarding the consequences on future fertility. Andrologia. 2015 Oct     [PubMed PMID: 25220690]
[110] Ohlander SJ,Lindgren MC,Lipshultz LI, Testosterone and Male Infertility. The Urologic clinics of North America. 2016 May     [PubMed PMID: 27132576]
[111] Bouloux P,Warne DW,Loumaye E, Efficacy and safety of recombinant human follicle-stimulating hormone in men with isolated hypogonadotropic hypogonadism. Fertility and sterility. 2002 Feb     [PubMed PMID: 11821082]
[112] Boeri L,Capogrosso P,Salonia A, Gonadotropin Treatment For The Male Hypogonadotropic Hypogonadism. Current pharmaceutical design. 2020 May 23     [PubMed PMID: 32445446]
[113] McGriff SC,Lo EM,Hotaling JM,Pastuszak AW, Optimal Endocrine Evaluation and Treatment of Male Infertility. The Urologic clinics of North America. 2020 May     [PubMed PMID: 32272985]
[114] Jefferys A,Siassakos D,Wardle P, The management of retrograde ejaculation: a systematic review and update. Fertility and sterility. 2012 Feb;     [PubMed PMID: 22177462]
[115] Mehta A,Sigman M, Management of the dry ejaculate: a systematic review of aspermia and retrograde ejaculation. Fertility and sterility. 2015 Nov     [PubMed PMID: 26432530]
[116] Avellino GJ,Lipshultz LI,Sigman M,Hwang K, Transurethral resection of the ejaculatory ducts: etiology of obstruction and surgical treatment options. Fertility and sterility. 2019 Mar     [PubMed PMID: 30827517]
[117] Fisch H,Kang YM,Johnson CW,Goluboff ET, Ejaculatory duct obstruction. Current opinion in urology. 2002 Nov     [PubMed PMID: 12409882]
[118] Lotti F,Corona G,Cocci A,Cipriani S,Baldi E,Degl'Innocenti S,Franco PN,Gacci M,Maggi M, The prevalence of midline prostatic cysts and the relationship between cyst size and semen parameters among infertile and fertile men. Human reproduction (Oxford, England). 2018 Nov 1     [PubMed PMID: 30285122]
[119] Paick JS, Transurethral resection of the ejaculatory duct. International journal of urology : official journal of the Japanese Urological Association. 2000 May     [PubMed PMID: 10830818]
[120] Chen SS, Significant predictive factors for subfertility in patients with subclinical varicocele. Andrologia. 2017 Dec     [PubMed PMID: 28295474]
[121] Tiseo BC,Esteves SC,Cocuzza MS, Summary evidence on the effects of varicocele treatment to improve natural fertility in subfertile men. Asian journal of andrology. 2016 Mar-Apr     [PubMed PMID: 26806080]
[122] Kroese AC,de Lange NM,Collins J,Evers JL, Surgery or embolization for varicoceles in subfertile men. The Cochrane database of systematic reviews. 2012 Oct 17     [PubMed PMID: 23076888]
[123] Li H,Dubocq F,Jiang Y,Tiguert R,Gheiler EL,Dhabuwala CB, Effect of surgically induced varicocele on testicular blood flow and Sertoli cell function. Urology. 1999 Jun     [PubMed PMID: 10367865]
[124] Tarhan S,Gümüs B,Gündüz I,Ayyildiz V,Göktan C, Effect of varicocele on testicular artery blood flow in men--color Doppler investigation. Scandinavian journal of urology and nephrology. 2003     [PubMed PMID: 12745742]
[125] Belker AM,Thomas AJ Jr,Fuchs EF,Konnak JW,Sharlip ID, Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study Group. The Journal of urology. 1991 Mar     [PubMed PMID: 1997700]
[126] Hsiao W,Sultan R,Lee R,Goldstein M, Increased follicle-stimulating hormone is associated with higher assisted reproduction use after vasectomy reversal. The Journal of urology. 2011 Jun     [PubMed PMID: 21497850]
[127] Namekawa T,Imamoto T,Kato M,Komiya A,Ichikawa T, Vasovasostomy and vasoepididymostomy: Review of the procedures, outcomes, and predictors of patency and pregnancy over the last decade. Reproductive medicine and biology. 2018 Oct     [PubMed PMID: 30377390]
[128] Farber NJ,Flannigan R,Srivastava A,Wang H,Goldstein M, Vasovasostomy: kinetics and predictors of patency. Fertility and sterility. 2020 Apr     [PubMed PMID: 32228879]
[129] Zarinara A,Zeraati H,Kamali K,Mohammad K,Rahmati M,Akhondi MM, The Success Rate and Factors Affecting the Outcome of Assisted Reproductive Treatment in Subfertile Men. Iranian journal of public health. 2020 Feb     [PubMed PMID: 32461941]
[130] de Angelis C,Galdiero M,Pivonello C,Garifalos F,Menafra D,Cariati F,Salzano C,Galdiero G,Piscopo M,Vece A,Colao A,Pivonello R, The role of vitamin D in male fertility: A focus on the testis. Reviews in endocrine & metabolic disorders. 2017 Sep     [PubMed PMID: 28667465]