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Male infertility
Male infertility
Male infertility
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Male infertility
SpecialtyUrology

Male infertility refers to a sexually mature male's inability to impregnate a fertile female.[1] Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children.[2] It affects approximately 7% of all men.[3] Male infertility is commonly due to deficiencies in the semen. Semen quality is used as a surrogate measure of male fecundity.[4] More recently,[as of?] advanced sperm analyses that examine intracellular sperm components are being developed.[5][6]

Age considerations

[edit]

Sperm motility increases from puberty through one's mid-thirties. Research shows that, from the age of 36 onwards, sperm motility decreases from 40% Grade A & B to 31% in one's 50s. The effects of aging on semen quality is summarized below based on a study of 1,219 subjects:[7]

Age group (years) Number of subjects (n) Motility (% Grade A+B)

[Min-Max]

21–28 57 47.5 ± 25.4

[0-88]

29–35 450 48.1 ± 30.4

[0-95]

36–42 532 40.0 ± 27.1

[0-83]

43–49 165 33.1 ± 25.1

[0-84]

50–60 15 31.3 ± 23.9

[0-59]

90% of seminiferous tubules in men in their 20s and 30s contain spermatids, whereas men in their 40s and 50s have spermatids in 50% of their seminiferous tubules, and only 10% of seminiferous tubules from men aged over 80 contain spermatids.[8][9] In a random international sample of 11,548 men confirmed to be biological fathers by DNA paternity testing, the oldest father was found to be 66 years old at the birth of his child. The ratio of DNA-confirmed versus DNA-rejected paternity tests around that age is in agreement with the notion of general male infertility above age 65–66.[10][11]

Causes

[edit]

Factors relating to male infertility include:[12]

Immune infertility

[edit]

Antisperm antibodies (ASA) have been considered as the cause of infertility in around 10–30% of infertile couples.[13] ASA production are directed against surface antigens on sperm, which can interfere with sperm motility and transport through the female reproductive tract, inhibiting capacitation and acrosome reaction, impaired fertilization, influence on the implantation process, and impaired growth and development of the embryo. Risk factors for the formation of antisperm antibodies in men include the breakdown of the blood‑testis barrier, trauma and surgery, orchitis, varicocele, infections, prostatitis, testicular cancer, failure of immunosuppression and unprotected receptive anal or oral sex with men.[13][14]

Genetics

[edit]
See also: Genetics of infertility

Chromosomal anomalies and genetic mutations account for nearly 10–15% of all male infertility cases.[15]

Mitochondrial DNA

[edit]

Mature human sperm contains almost no mitochondrial DNA at all. An increased amount of mitochondrial DNA in the sperm cells has shown to have a negative impact on fertility.[16][17]

Klinefelter syndrome

[edit]

One of the most commonly known causes of infertility is Klinefelter syndrome, which affects one in 500–1000 newborn males.[18] Klinefelter syndrome is a chromosomal defect that occurs during gamete formation due to a non-disjunction error during cell division. This results in males having smaller testes, reducing the amount of testosterone and sperm production.[19] Males with this syndrome carry an extra X chromosome (XXY), meaning they have 47 chromosomes compared to the normal 46 in each cell. This extra chromosome directly affects sexual development before birth and during puberty. A variation of Klinefelter syndrome is when some cells in an individual have the extra X chromosome but others do not, referred to as mosaic Klinefelter syndrome. The reduction of testosterone in the male body normally results in an overall decrease in the production of viable sperm for these individuals, thereby making it hard for them to father children without fertility treatment.[18]

Y chromosome deletions

[edit]

Y chromosomal infertility is a direct cause of male infertility due to its effects on sperm production, occurring in approximately one in 2000 males.[20] Usually, affected men show no symptoms, although they may have smaller testes. Men with this condition may exhibit azoospermia (no sperm production), oligozoospermia (small number of sperm production), or they may produce abnormally shaped sperm (teratozoospermia).[20] This case of infertility occurs during the development of gametes in the male. Where a normal healthy male will have both an X and a Y chromosome, affected males have genetic deletions in the Y chromosome. These deletions affect protein production that is vital for spermatogenesis. Studies have shown that this is an inherited trait; if a male is fathered by a man who also exhibited Y chromosome deletions then this trait will be passed down.[citation needed] These individuals are thereby "Y-linked". Daughters are not affected and cannot be carriers due to their lack of a Y chromosome.

Other

[edit]

Pre-testicular causes

[edit]

Pre-testicular factors refer to conditions that impede adequate support of the testes and include situations of poor hormonal support and poor general health including:

Tobacco smoking

[edit]
See also: Smoking and pregnancy

There is increasing evidence that the harmful products of tobacco smoking may damage the testicles[32] and kill sperm,[33][34] but their effect on male fertility is not clear.[35] Some governments require manufacturers to put warnings on packets. Smoking tobacco increases intake of cadmium, because the tobacco plant absorbs the metal. Cadmium, being chemically similar to zinc, may replace zinc in the DNA polymerase, which plays a critical role in sperm production. Zinc replaced by cadmium in DNA polymerase can be particularly damaging to the testes.[36]

DNA damage

[edit]

Common inherited variants in genes that encode enzymes employed in DNA mismatch repair are associated with increased risk of sperm DNA damage and male infertility.[37] As men age there is a consistent decline in semen quality, and this decline appears to be due to DNA damage.[38] The damage manifests by DNA fragmentation and by the increased susceptibility to denaturation upon exposure to heat or acid, the features characteristic of apoptosis of somatic cells.[39] These findings suggest that DNA damage is an important factor in male infertility.[citation needed]

Epigenetic

[edit]
See also: DNA methylation

An increasing amount of recent evidence has been recorded documenting abnormal sperm DNA methylation in association with abnormal semen parameters and male infertility.[40][41] Until recently, scientists have thought that epigenetic markers only affect the individual and are not passed down due to not changing the DNA.[42] New studies suggest environmental factors that changed an individual's epigenetic markers can be seen in their grandchildren, one such study demonstrating this through rats and fertility disruptors.[42] Another study bred rats exposed to an endocrine disruptor, observing effects up to generation F5 including decreased sperm motility and decreased sperm count.[43] These studies suggest that environmental factors that influence fertility can be felt for generations even without changing the DNA.[citation needed]

Post-testicular causes

[edit]

Post-testicular factors decrease male fertility due to conditions that affect the male genital system after testicular sperm production and include defects of the genital tract as well as problems in ejaculation:[citation needed]

Diagnostic evaluations

[edit]

The diagnosis of infertility begins with a medical history and physical exam by a physician, physician assistant, or nurse practitioner. Typically two separate semen analyses will be required. The provider may order blood tests to look for hormone imbalances, medical conditions, or genetic issues.[citation needed]

Medical history

[edit]

The history should include prior testicular or penile insults (torsion, cryptorchidism, trauma), infections (mumps orchitis, epididymitis), environmental factors, excessive heat, radiation, medications, and drug use (anabolic steroids, selective serotonin reuptake inhibitors, alcohol, smoking). Sexual habits, frequency and timing of intercourse, use of lubricants, and each partner's previous fertility experiences are important. Loss of libido and headaches or visual disturbances may indicate a pituitary tumor.[citation needed]

The past medical or surgical history may reveal thyroid or liver disease (abnormalities of spermatogenesis), diabetic neuropathy (retrograde ejaculation), radical pelvic or retroperitoneal surgery (absent seminal emission secondary to sympathetic nerve injury), or hernia repair (damage to the vas deferens or testicular blood supply).[citation needed]

A family history may reveal genetic problems.

Physical examination

[edit]

Usually, the patient disrobes completely and puts on a gown. The physician, physician assistant, or nurse practitioner will perform a thorough examination of the penis, scrotum, testicles, vas deferens, spermatic cords, ejaculatory ducts, urethra, urinary bladder, anus and rectum. An orchidometer can measure testicular volume, which in turn is tightly associated with both sperm and hormonal parameters.[3] A physical exam of the scrotum can reveal a varicocele, but the impact of detecting and surgically correcting a varicocele on sperm parameters or overall male fertility is debated.[3]

Sperm sample

[edit]

Semen sample obtaining

[edit]

Semen sample obtaining is the first step in spermiogram. The optimal sexual abstinence for semen sample obtaining is of 2–7 days. The first way to obtain the semen sample is through masturbation, and the best place to obtain it is in the same clinic, as this way temperature changes during transport can be avoided, which can be lethal for some spermatozoa.

A single semen sample is not determining for disease diagnosis, so two different samples have to be analyzed with an interval between them of seven days to three months, as sperm production is a cyclic process. It is prudent to ask about possible sample loss, as that could mask true results of spermiogram.

To obtain the sample, a sterile plastic recipient is put directly inside, always no more than one hour before being studied. Conventional preservatives should not be used, as they have chemical substances as lubricants or spermicides that could damage the sample. If preservatives have to be used, for cases of religious ethics in which masturbation is forbidden, a preservative with holes is used. In case of paraplegia it is possible to use mechanic tools or electroejaculation.

The sample should never be obtained through coitus interruptus for several reasons:

  • Some part of ejaculation could be lost.
  • Bacterial contamination could happen.
  • The acid vaginal pH could be deleterious for sperm motility.

Also is very important to label the sample correctly the recipient with patient identification, date, hour, abstinence days, among other data required to be known.

Main article: Semen analysis
Further information: Semen quality

The volume of the semen sample (must be more than 1.5 ml), approximate number of total sperm cells, sperm motility/forward progression, and % of sperm with normal morphology are measured. It is possible to have hyperspermia (high volume more than 6 ml) or Hypospermia (low volume less than 0.5 ml). This is the most common type of fertility testing.[44][45] Semen deficiencies are often labeled as follows:

  • Oligospermia or oligozoospermia – decreased number of spermatozoa in semen
  • Aspermia – complete lack of semen
  • Hypospermia – reduced seminal volume
  • Azoospermia – absence of sperm cells in semen
  • Teratospermia – increase in sperm with abnormal morphology
  • Asthenozoospermia – reduced sperm motility
  • Necrozoospermia – all sperm in the ejaculate are dead
  • Leucospermia – a high level of white blood cells in semen
  • Normozoospermia or normospermia – It is a result of semen analysis that shows normal values of all ejaculate parameters by WHO but still there are chances of being infertile. This is also called as unexplained Infertility[citation needed]

There are various combinations of these as well, e.g. Teratoasthenozoospermia, which is reduced sperm morphology and motility. Low sperm counts are often associated with decreased sperm motility and increased abnormal morphology, thus the terms "oligoasthenoteratozoospermia" or "oligospermia" can be used as a catch-all.

Special obtaining

[edit]
  • Psychological inhibition
  • Psychotherapy
  • Intercourse with special preservatives without lubricants or spermicides. In case of religious limitations, the use of Seminal Collection Devices (SCDs), such as preservatives with holes, is recommended.
  • Drug stimulation
  • Percutaneous spermatozoa obtaining directly from epididymis, testes, etc.
  • Neurological injury
  • Vibro-stimulation
  • Electro-stimulation
  • Retrograde ejaculation
    • This type of ejaculation happens when there is a defect on prostate, so the sample is not ejaculated outside but to the bladder. In that case, sperm is instead collected by neutralizing acidity in the bladder and collecting urine samples after ejaculation.

Blood sample

[edit]

Common hormonal test include determination of FSH and testosterone levels. A blood sample can reveal genetic causes of infertility, e.g. Klinefelter syndrome, a Y chromosome microdeletion, or cystic fibrosis.[citation needed]

Ultrasonography

[edit]

Scrotal ultrasonography is useful when there is a suspicion of some particular diseases. It may detect signs of testicular dysgenesis, which is often related to an impaired spermatogenesis and to a higher risk of testicular cancer.[3] Scrotum ultrasonography may also detect testicular lesions suggestive of malignancy. A decreased testicular vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions such as lymphoma and leukemia.[3] Doppler ultrasonography useful in assessing venous reflux in case of a varicocele, when palpation is unreliable or in detecting recurrence or persistence after surgery, although the impact of its detection and surgical correction on sperm parameters and overall fertility is debated.[3]

Dilation of the head or tail of the epididymis is suggestive of obstruction or inflammation of the male reproductive tract.[3] Such abnormalities are associated with abnormalities in sperm parameters, as are abnormalities in the texture of the epididymis.[3] Scrotal and transrectal ultrasonography (TRUS) are useful in detecting uni- or bilateral congenital absence of the vas deferens (CBAVD), which may be associated with abnormalities or agenesis of the epididymis, seminal vesicles or kidneys, and indicate the need for testicular sperm extraction.[3] TRUS plays a key role in assessing azoospermia caused by obstruction, and detecting distal CBAVD or anomalies related to obstruction of the ejaculatory duct, such as abnormalities within the duct itself, a median cyst of the prostate (indicating a need for cyst aspiration), or an impairment of the seminal vesicles to become enlarged or emptied.[3]

Hyposmotic test

[edit]

To check if the plasma membrane of the sperm is working properly or if it is damaged. To do this, the spermatozoa are placed in a hypotonic medium (low in salts), which causes an osmotic imbalance in the cells, causing the medium to enter the interior of the spermatozoon and swell it. If the sperm membrane is damaged, it will not be functional, so fertilization cannot take place. Hence the relevance of this test.[46]

Sperm FISH

[edit]

To check if the spermatozoa have a normal set of chromosomes. It provides great information about the seminal quality of the male. It is performed by marking specific chromosomes of the sperm with fluorescent DNA probes. Some situations in which sperm FISH is indicated are the following:

-Alterations in the karyotype. -Altered seminogram, especially in cases with low concentration or serious morphology problems. -Man undergoing chemotherapy or radiotherapy. -Couples with recurrent miscarriages of unknown cause. -Implantation failure on repeated occasions after applying assisted reproductive techniques. -Couples who have had a child with some chromosomal alteration. Advanced age.[47]

Prevention

[edit]

Some strategies suggested or proposed for avoiding male infertility include the following:

  • Avoiding smoking[48] as it damages sperm DNA
  • Avoiding heavy marijuana and alcohol use.[49]
  • Avoiding excessive heat to the testes.[49]
  • Maintaining optimal frequency of coital activity: sperm counts can be depressed by daily coital activity[49] and sperm motility may be depressed by coital activity that takes place too infrequently (abstinence 10–14 days or more).[49]
  • Wearing a protective cup and jockstrap to protect the testicles, in any sport such as baseball, football, cricket, lacrosse, hockey, softball, paintball, rodeo, motocross, wrestling, soccer, karate or other martial arts or any sport where a ball, foot, arm, knee or bat can come into contact with the groin.
  • Diet: Healthy diets (i.e. the Mediterranean diet[50]) rich in such nutrients as omega-3 fatty acids, some antioxidants and vitamins, and low in saturated fatty acids (SFAs) and trans-fatty acids (TFAs) are inversely associated with low semen quality parameters. In terms of food groups, fish, shellfish and seafood, poultry, cereals, vegetables and fruits, and low-fat dairy products have been positively related to sperm quality. However, diets rich in processed meat, soy foods, potatoes, full-fat dairy products, coffee, alcohol and sugar-sweetened beverages and sweets have been inversely associated with the quality of semen in some studies. The few studies relating male nutrient or food intake and fecundability also suggest that diets rich in red meat, processed meat, tea and caffeine are associated with a lower rate of fecundability. This association is only controversial in the case of alcohol. The potential biological mechanisms linking diet with sperm function and fertility are largely unknown and require further study.[51]

Treatment

[edit]

Treatments vary according to the underlying disease and the degree of the impairment of the male's fertility. Further, in an infertility situation, the fertility of the female needs to be considered.[52]

Pre-testicular conditions can often be addressed by medical means or interventions.

Testicular-based male infertility tends to be resistant to medication. Usual approaches include using the sperm for intrauterine insemination (IUI), in vitro fertilization (IVF), or IVF with intracytoplasmatic sperm injection (ICSI). With IVF-ICSI even with a few sperm pregnancies can be achieved.

Obstructive causes of post-testicular infertility can be overcome with either surgery or IVF-ICSI. Ejaculatory factors may be treatable by medication, or by IUI therapy or IVF.

Vitamin E helps counter oxidative stress,[53] which is associated with sperm DNA damage and reduced sperm motility.[54][55] A hormone-antioxidant combination may improve sperm count and motility.[56][55] Giving oral antioxidants to men in couples undergoing in vitro fertilisation for male factor or unexplained subfertility may lead to an increase in the live birth rate but overall the risk of adverse effects is unclear.[57]

Hormonal therapy

[edit]
See also: Spermatogenesis § Hormonal control

Administration of luteinizing hormone (LH) (or human chorionic gonadotropin) and follicle-stimulating hormone (FSH) is very effective in the treatment of male infertility due to hypogonadotropic hypogonadism.[58] Although controversial,[59] off-label clomiphene citrate, an antiestrogen, may also be effective by elevating gonadotropin levels.[58]

Though androgens are absolutely essential for spermatogenesis and therefore male fertility, exogenous testosterone therapy has been found to be ineffective in benefiting men with low sperm count.[60] This is thought to be because very high local levels of testosterone in the testes (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels)[61] are required to mediate spermatogenesis, and exogenous testosterone therapy (which is administered systemically) cannot achieve these required high local concentrations (at least not without extremely supraphysiological dosages).[60] Moreover, exogenous androgen therapy can actually impair or abolish male fertility by suppressing gonadotropin secretion from the pituitary gland, as seen in users of androgens/anabolic steroids (who often have partially or completely suppressed sperm production).[58][60] This is because suppression of gonadotropin levels results in decreased testicular androgen production (causing diminished local concentrations in the testes)[58][60] and because FSH is independently critical for spermatogenesis.[62][63] In contrast to FSH, LH has little role in male fertility outside of inducing gonadal testosterone production.[64]

Estrogen, at some concentration, has been found to be essential for male fertility/spermatogenesis.[65][66] However, estrogen levels that are too high can impair male fertility by suppressing gonadotropin secretion and thereby diminishing intratesticular androgen levels.[60] As such, clomiphene citrate (an antiestrogen) and aromatase inhibitors such as testolactone or anastrozole have shown effectiveness in benefiting spermatogenesis.[60]

Low-dose estrogen and testosterone combination therapy may improve sperm count and motility in some men,[67] including in men with severe oligospermia.[68]

Research

[edit]

Researchers at Münster University developed in vitro culture conditions using a three-dimensional agar culture system which induces mouse testicular germ cells to reach the final stages of spermatogenesis, including spermatozoa generation.[69] If reproduced in humans, this could potentially enable infertile men to father children with their own sperm.[70][71]

Researchers from Montana State University developed precursors of sperm from skin cells of infertile men.[72][73][74]

Sharpe et al. comment on the success of intracytoplasmic sperm injection (ICSI) in women saying, "[t]hus, the woman carries the treatment burden for male infertility, a fairly unique scenario in medical practice. Ironically, ICSI's success has effectively diverted attention from identifying what causes male infertility and focused research onto the female, to optimize the provision of eggs and a receptive endometrium, on which ICSI's success depends."[75][76]

Prevalence

[edit]

Currently, there are no solid numbers on how many couples worldwide experience infertility, but the World Health Organization estimates between 60 and 80 million couples are affected. The population in different regions have varying amounts of infertility.

Starting in the late 20th century, scientists have expressed concerns about the declining semen quality in men. A study was done in 1992 with men who had never experienced infertility showed that the amount of sperm in semen had declined by 1% per year since 1938.[77][78] Further research a few years later also confirmed the decline in sperm count and also seminal volume.[79] Various studies in Finland, Southern Tunisia, and Argentina also showed a decline in sperm count, motility, morphology, and seminal volume.

Males from India had a 30.3% decline in sperm count, 22.9% decline in sperm motility, and a 51% decrease in morphology over a span of a decade. Doctors in India disclosed that the sperm count of a fertile Indian male had decreased by a third over a span of three decades.[80] Some factors may include exposure to high temperatures at places such as factories. A 1 degree increase in temperature will reduce 14% of spermatogenesis.[81]

Researchers in Calcutta conducted a study between 1981 and 1985 that also showed a decrease in sperm motility and seminal volume, but no change in sperm concentration.[82]

Society and culture

[edit]
Main article: Infertility and childlessness stigmas

There are a variety of social stigmas that surround male infertility throughout the world. The condition and its effects on both men and women is the topic for example of the novel set in Nigeria entitled, The Secret Lives of Baba Segin's Wives. A lot of research has pointed to the relationship between infertility and emasculation.[83][84][85] This association has led to infertility being less studied and diagnosed in men over time.[86] In places like Egypt,[84] Zimbabwe,[83] and Mexico,[87] erectile dysfunction, also known as impotence, is considered a determinant of infertility. When stereotypical ideals of manhood are virility and strength, men sharing problems of infertility can face feelings of inadequacy, unworthiness, and have thoughts of suicide.[88] In many cases, a variety of socio-economic interventions come in play to determine penile activity. For the Shona people, since impotence is linked to infertility, an examination to check on the penile function spans from infancy to post marriage.[83] At infancy, there are daily check-ups by the mothers on the son's erection and urine quality.[83] When the son reaches puberty, they are asked to ejaculate in river banks and for their male elders to examine sperm quality.[83] The traditions last until post-marriage, when the family of the bride take part to check on consummation and the groom's sperm quality.[83]

Crisis

[edit]
This section is an excerpt from Male infertility crisis.[edit]

The male infertility crisis is an increase in male infertility since the mid-1970s.[89] The issue attracted media attention after a 2017 meta-analysis found that sperm counts in Western countries had declined by 52.4 percent between 1973 and 2011.[90][91] The decline is particularly prevalent in Western regions such as New Zealand, Australia, Europe, and North America.[92] A 2022 meta-analysis reported that this decline extends to non-Western countries, namely those in Asia, Africa, Central America, and South America.[93] This meta-analysis also suggests that the decline in sperm counts may be accelerating.[93]

This decline in male fertility is the subject of research and debate. Proposed explanations include lifestyle factors, such as changes in diet and physical activity levels, and increased exposure to endocrine disrupting chemicals, such as those found in plastics and pesticides.[94][95] Several studies also indicate that warmer temperatures, as a result of manmade climate change, may be playing a role.[96] Some scientists[97][98] have questioned the extent of the crisis; the scientific community, however, generally acknowledges increasing male infertility as a men's-health issue.[99]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Male infertility

View on Grokipedia
from Grokipedia
Male infertility is defined as the inability of a male to achieve a pregnancy in a fertile female partner after at least 12 months of regular, unprotected sexual intercourse. It contributes to approximately 50% of all couple infertility cases worldwide, with male factors solely responsible in 20-30% of instances. Globally, the prevalence exceeded 56 million cases in 2019, reflecting a rising burden amid broader declines in semen quality observed in population studies. The condition arises from disruptions in , sperm transport, or delivery, often involving quantitative defects such as (low sperm count) or (absence of sperm), alongside qualitative issues like impaired or morphology. Common identifiable causes include varicoceles (dilated scrotal veins affecting up to 35% of primary infertility cases), genetic abnormalities (e.g., anomalies in 5-10% of affected men), hormonal deficiencies, and obstructions from congenital or acquired anomalies. Environmental and lifestyle factors, including exposure to endocrine disruptors, , , and , exacerbate risk, though 30-40% of cases remain idiopathic despite evaluation.00148-4/pdf) Treatable etiologies account for about 18% of diagnoses, underscoring the potential for interventions like varicocelectomy or assisted reproductive technologies, yet outcomes vary due to underlying causal heterogeneity. Emerging data also link suboptimal parameters to elevated all-cause mortality, suggesting male infertility as a marker of systemic compromise.

Definition and Physiology

Definition and Scope

Male infertility refers to the inability of a sexually mature male to achieve pregnancy in a fertile female partner after at least 12 months of regular, unprotected sexual intercourse. This definition aligns with clinical standards from organizations such as the American Urological Association and encompasses conditions impairing sperm production, function, or delivery, rather than solely focusing on sperm count abnormalities. Primary male infertility denotes cases with no prior conception, while secondary infertility involves prior successful reproduction followed by subsequent failure. In scope, male infertility contributes to approximately 50% of couple infertility cases worldwide, with male factors solely responsible in about 20% and contributory alongside factors in 30-40% of instances. Globally, affects an estimated 15% of couples, equating to roughly 48.5 million couples, with male-specific issues implicated in a significant portion based on and diagnostic evaluations. Recent estimates from 2021 indicate over 55 million men aged 15-49 living with , reflecting a burden that has increased by about 75% since 1990 in terms of cases and disability-adjusted life years. This scope includes both obstructive and non-obstructive etiologies, such as low sperm concentration (), absent sperm (), poor motility (asthenospermia), or abnormal morphology (), often identified through semen parameter thresholds updated in 2021. The condition's evaluation typically begins with medical history, physical examination, and semen analysis, distinguishing it from by focusing on male reproductive tract integrity and gamete quality. While treatable in many cases through modifications, , or assisted reproductive technologies, untreated male infertility can lead to persistent subfertility, underscoring its role as a key determinant in couple reproductive outcomes rather than an isolated male issue.

Normal Spermatogenesis and Fertility Mechanisms

, the production of mature spermatozoa, occurs continuously within the seminiferous tubules of the testes, beginning at and persisting throughout adult life under normal conditions. This process involves three main phases: proliferative mitotic divisions of spermatogonial s, meiotic divisions to produce haploid spermatids, and , where spermatids differentiate into spermatozoa without further . Spermatogonia, the diploid germ cells adjacent to the , undergo to maintain a stem cell pool and generate type A and B spermatogonia; type B cells then commit to , forming primary spermatocytes that undergo and the first meiotic division to yield secondary spermatocytes, followed by the second division producing round spermatids. During , these haploid cells undergo extensive morphological changes, including nuclear condensation, formation from Golgi-derived vesicles, development, and cytoplasmic reduction, resulting in streamlined spermatozoa capable of . The entire process in humans takes approximately 64-74 days from spermatogonium to mature release into the tubule lumen. Hormonal regulation is essential for initiating and sustaining spermatogenesis via the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH); FSH acts on Sertoli cells to support germ cell proliferation and maturation by promoting nutrient provision and blood-testis barrier formation, while LH stimulates Leydig cells to produce testosterone. Testosterone, at high intratesticular concentrations (often 50-100 times serum levels), is critical for meiosis progression, spermiogenesis, and Sertoli cell function, acting via androgen receptors to regulate gene expression in both Sertoli and germ cells. Inhibin B, secreted by Sertoli cells, provides negative feedback to the pituitary to modulate FSH levels, ensuring balanced germ cell production. Disruptions in this axis, such as low FSH or testosterone, halt spermatogenesis at specific stages, underscoring the axis's causal role in fertility. Post-testicular sperm maturation occurs in the , where immotile testicular spermatozoa acquire forward , fertilizing capacity, and resistance to the tract environment over 10-14 days of transit. Epididymal epithelial cells secrete proteins and glycans that remodel the plasma , enhance mitochondrial function for ATP production, and stabilize the . Mature are stored in the cauda epididymis until , triggered by , propels —comprising ~5% and 95% seminal plasma from and —through the and . In the reproductive tract, undergo , involving cholesterol efflux, protein tyrosine phosphorylation, and hyperactivated , preparing them for zona pellucida (ZP) binding. Fertilization requires the , where ZP glycoproteins induce calcium influx and of acrosomal enzymes to penetrate the ZP, followed by -oolemma fusion and via zeta-mediated oscillations. Successful fertilization yields a diploid , with normal parameters including concentration >15 million/mL, >40%, and morphology >4% normal forms per standards.

Epidemiology

Global and Regional Prevalence

Male infertility contributes to approximately 30-50% of all cases worldwide, with overall couple affecting 8-12% of reproductive-aged couples.32667-2/abstract) In absolute terms, the global prevalence of male infertility in 2019 was estimated at 56.5 million cases among males aged 15-49 years (95% uncertainty interval: 31.9-90.2 million), reflecting an increase from earlier decades driven by and rising incidence rates. By 2021, this burden had grown to over 55 million cases, with disability-adjusted life years (DALYs) exceeding 300,000, marking a 74.7% rise in cases since 1990. These figures derive from Global Burden of Disease (GBD) analyses, which incorporate data from semen analyses, self-reports, and clinical registries, though underreporting persists in low-resource settings due to limited access to diagnostics. Regional variations show higher absolute burdens in populous areas like , where accounted for about 14.6 million cases in 2019, comprising roughly 26% of the global total, despite stable per-capita rates over time. In contrast, prevalence rates per 100,000 population tend to be elevated in parts of and the /, with age-standardized rates reaching 3,510 per 100,000 in the and similarly high in and within the region. Western and report lower absolute numbers but comparable or slightly higher diagnostic rates due to better healthcare access, with male factor identified in 20-40% of evaluated cases. Sub-Saharan and parts of exhibit lower documented prevalence, potentially attributable to cultural stigma, underdiagnosis, and reliance on traditional remedies rather than formal , leading to epidemiological gaps. Overall, socioeconomic disparities amplify burdens in low- and middle-income regions, where environmental and factors exacerbate trends. Advanced paternal age contributes to declines in multiple parameters, including reductions in volume, total count, progressive and total , and normal morphology, alongside increases in DNA fragmentation. These changes are linked to accumulating , mitochondrial dysfunction, and impaired mechanisms in germ cells. A of studies from 2014 onward confirmed consistent declines in volume across 7 of 9 analyses and in 9 of 10, with DNA fragmentation elevated in all 11 examined datasets. concentration often remains stable through the 30s and into the 40s, though overall fertility potential diminishes as other parameters deteriorate. Quantitative meta-analyses quantify these shifts: men over 50 exhibit a 3–22% decrease in semen volume, 3–37% in sperm motility, and 4–18% in normal morphology relative to younger cohorts, with declines accelerating after age 34. The DNA fragmentation index rises markedly after age 40, with significant elevations (p < 0.001) compared to men under 40, reflecting progressive chromatin packaging defects and unrepaired strand breaks. Motility peaks before age 30 and drops significantly thereafter, particularly post-35 (p < 0.05). These alterations correlate with higher reactive oxygen species levels and epigenetic changes, such as annual increases of 1.76% in 5-methylcytosine and nearly 5% in 5-hydroxymethylcytosine. Reproductive outcomes reflect these impairments, with advanced paternal age prolonging time to natural pregnancy—18–28% of men aged 35–40 fail to conceive within 12 cycles—and elevating miscarriage odds (1.43-fold at age ≥45 versus 1.04 at 30–34). In assisted reproduction, pregnancy rates drop 23–38% for men over 50 compared to those under 30, and live birth rates decline in IVF/ICSI cycles for men ≥40, especially when partnered with women aged 35–39, independent of diagnosed male infertility. While some analyses report no direct translation to assisted pregnancy rates despite poorer semen metrics, the broader evidence indicates reduced fertilization efficiency and embryo viability due to paternal age effects. A 2022 meta-regression analysis of 223 studies involving over 57,000 men from 53 countries reported a significant decline in sperm concentration (SC) of 51.6% and total sperm count (TSC) of 62.3% globally between 1973 and 2018, with the rate of decline accelerating after 2000, particularly in Western countries where SC fell from 99 million/ml to 47 million/ml. This update built on a prior 2017 analysis limited to North America, Europe, and Australia, which had documented a 52.4% SC decline and 59.3% TSC decline from 1973 to 2011, highlighting methodological improvements such as exclusion of selected clinical samples to reduce bias. The analysis controlled for covariates like age, abstinence period, and geographic location, attributing the trends to environmental and lifestyle factors rather than artifacts of study design. Semen quality parameters beyond count have shown parallel declines in multiple regional studies. A 2022 spatiotemporal analysis across continents found reductions in progressive motility and morphology, with SC dropping by approximately 50% in some cohorts from the mid-20th century to 1990, corroborated by data from unselected young men in Europe and Asia. In Southern Europe, a 2022 study of over 10,000 samples from 2000 to 2020 observed stable SC but significant decreases in motility (from 45% to 38% progressive) and normal morphology (from 7% to 5%), independent of age or comorbidities. Globally, a 2023 systematic review of young men confirmed deteriorating semen quality, including lower volume and vitality, across 201 studies from 2000 onward, though heterogeneity in measurement protocols complicates direct comparisons. Controversy persists due to methodological challenges, including reliance on fertility clinic samples prone to selection bias and variations in semen analysis techniques over time. A 2024 U.S. study of 1,000 fertile men found stable SC (median 56 million/ml) from 2017 to 2023, arguing against a universal crisis and attributing meta-analytic declines to overrepresentation of subfertile populations. Similarly, a 2024 Manchester analysis of 6,946 unselected Danish men reported no overall SC drop from 2017 to 2022, questioning acceleration claims and emphasizing intraindividual variability over temporal trends. Critics of decline narratives, including a 2021 review, highlight unadjusted confounders like rising obesity and inconsistent WHO reference values (e.g., SC threshold lowered from 20 million/ml in 2010 to 15 million/ml in 2021), which may inflate perceived deteriorations without proving causation. Despite these, meta-analyses incorporating unselected cohorts (e.g., military recruits, students) consistently detect declines exceeding measurement error, suggesting substantive trends warranting further causal investigation.

Etiology

Genetic and Chromosomal Abnormalities

Chromosomal abnormalities are detected in 5-15% of men presenting with severe oligozoospermia or azoospermia, with rates reaching 14.4% specifically among those with azoospermia. These include numerical and structural variants that disrupt meiosis, spermatogenesis, or sperm production, leading to impaired fertility. The most prevalent is sex chromosome aneuploidy, particularly (47,XXY karyotype or variants), which accounts for approximately 14% of cases of nonobstructive azoospermia (NOA) and arises from nondisjunction during meiosis. Affected individuals exhibit small testes, hypergonadotropic hypogonadism, and progressive germ cell depletion, resulting in azoospermia or severe oligozoospermia; general population incidence is 1 in 500-1,000 male births, but prevalence is markedly elevated (up to 10-fold) in infertile cohorts. Structural chromosomal aberrations, such as Robertsonian translocations, reciprocal translocations, and inversions, occur in 0.5-1% of the general male population but at higher frequencies (2-5%) among infertile men, often correlating with increased rates of chromosomally abnormal spermatozoa and recurrent pregnancy loss in partners. These rearrangements can interfere with meiotic pairing and segregation, though many carriers maintain some spermatogenic capacity. Less common aneuploidies, like 47,XYY, are associated with variable oligozoospermia but milder fertility impacts compared to XXY. Y-chromosome microdeletions represent the second most common genetic etiology after , affecting 7% of infertile men overall and 15-20% of those with azoospermia or severe oligozoospermia. These deletions occur via nonallelic homologous recombination in the AZF (azoospermia factor) regions of Yq11, with AZFc being the most frequent (~80% of cases), followed by AZFb (1-5%) and AZFa (0.5-4%). AZFa deletions cause complete germ cell aplasia (), AZFb lead to spermatogenic maturation arrest, and AZFc result in variable phenotypes ranging from azoospermia to oligozoospermia, as they remove multicopy genes essential for sperm production; transmission to male offspring via assisted reproduction necessitates counseling due to heritability. Monogenic disorders also contribute, notably mutations in the CFTR gene, which underlie congenital bilateral absence of the vas deferens (CBAVD) in 60-70% of cases—a condition accounting for 1-2% of overall male infertility but causing obstructive azoospermia through failed Wolffian duct development. CFTR dysfunction impairs electrolyte transport and fluid secretion in the reproductive tract, with common variants like F508del disrupting vas deferens embryogenesis; non-CFTR mutations (e.g., in ADGRG2) explain 11-15% of remaining CBAVD instances. Additional single-gene defects, such as TEX11 mutations (2.4% in NOA with meiotic arrest), target spermatogenic pathways but are rarer and often identified via targeted sequencing in idiopathic severe cases. Karyotyping and genetic screening are indicated for men with sperm counts below 5 million/mL to identify these etiologies, informing prognosis and reproductive options.

Anatomical and Structural Defects

Anatomical and structural defects in the male reproductive system contribute to infertility by disrupting spermatogenesis, sperm transport, or ejaculation, accounting for approximately 18% of treatable male infertility cases. These defects often manifest as congenital malformations or acquired obstructions, leading to conditions such as obstructive azoospermia or impaired testicular function. Common examples include varicoceles, cryptorchidism, and congenital absence of the vas deferens, each with distinct pathophysiological mechanisms rooted in vascular, developmental, or ductal anomalies. Varicocele, characterized by dilation of the pampiniform venous plexus in the scrotum, affects 15% of the general male population but rises to 35-40% among men with primary infertility. The condition elevates scrotal temperature, induces oxidative stress, and causes testicular hypoxia due to venous stasis, thereby impairing sperm production, motility, and DNA integrity. In infertile men, varicoceles correlate with reduced semen parameters, and surgical repair has been shown to improve fertility outcomes in select cases, though causality remains debated due to variable semen improvements post-intervention. Cryptorchidism, or undescended testes, is the most frequent congenital anomaly in male newborns, occurring in 1-4% at birth and persisting in 1% by age one after spontaneous descent or orchidopexy. It compromises fertility through elevated intratesticular temperature and disrupted germ cell development, resulting in infertility rates of 32% for unilateral cases and up to 59-75% for bilateral cases, even after surgical correction. Nearly 10% of men presenting with infertility report a history of cryptorchidism, with bilateral involvement conferring higher risks of azoospermia or severe oligospermia due to progressive tubular atrophy. Congenital bilateral absence of the vas deferens (CBAVD) causes obstructive azoospermia by preventing sperm transport from the epididymis to the ejaculatory ducts, accounting for 1-2% of male infertility cases and up to 6% of azoospermic men. Often associated with cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in 70-80% of cases, CBAVD leads to low-volume azoospermic semen with acidic pH due to absent seminal vesicle contributions, though spermatogenesis remains intact in the testes. Unilateral absence or segmental obstructions, such as epididymal cysts or prostatic midline cysts, similarly impair ductal patency and contribute to post-testicular infertility. Other structural anomalies, including hypospadias and ejaculatory duct obstructions, further exemplify how genitourinary birth defects link to infertility via impaired sperm delivery or associated testicular hypoplasia. These defects underscore the importance of early diagnosis, as many are identifiable via physical exam or imaging, enabling targeted interventions like microsurgical reconstruction to restore patency where feasible.

Infectious, Immune, and Inflammatory Causes

Infections of the male reproductive tract, particularly bacterial sexually transmitted infections such as and , ascend from the urethra to cause epididymitis, orchitis, or prostatitis, leading to ductal scarring, obstruction, and impaired spermatogenesis that manifests as obstructive azoospermia or severe oligozoospermia. Viral infections, including orchitis in post-pubertal males, directly damage seminiferous tubules and Leydig cells, resulting in atrophy and hypospermatogenesis; mumps-associated orchitis affects up to 38% of adult males with the disease and causes permanent infertility in approximately 30% of cases. Other viruses like human immunodeficiency virus (HIV) and have been detected in semen, correlating with reduced sperm motility and viability through mechanisms such as oxidative stress and apoptosis induction in germ cells. Bacterial pathogens, including and , prevalent in semen of infertile men at higher rates than in fertile controls, generate reactive oxygen species (ROS) that fragment sperm DNA and alter acrosomal integrity. Inflammatory conditions, often triggered by unresolved infections or idiopathic leukocytospermia (seminal white blood cell counts exceeding 1 million/mL), induce chronic genital tract inflammation that impairs sperm parameters via cytokine-mediated disruption of Sertoli cell function and excessive ROS production. Chronic prostatitis, affecting up to 50% of men with chronic pelvic pain syndrome, correlates with elevated seminal proinflammatory markers like interleukin-6 and tumor necrosis factor-alpha, which reduce sperm concentration and motility while promoting fibrosis in the prostate and seminal vesicles. Orchitis and epididymitis, whether infectious or autoimmune in origin, lead to tubular occlusion and germ cell loss, with histopathological evidence of lymphocytic infiltration and basement membrane thickening in affected testes. Non-infectious chronic inflammation contributes to 10-15% of male infertility cases by fostering a hostile seminal microenvironment that agglutinates spermatozoa and accelerates capacitation defects. Immune-mediated infertility arises primarily from antisperm antibodies (ASAs), which bind sperm surface antigens and cause agglutination, impaired motility, and phagocytosis by leukocytes, with prevalence ranging from 2.6% to 6.6% among infertile men using World Health Organization thresholds for mixed antiglobulin reaction testing. ASAs often develop following breaches in the blood-testis barrier due to trauma, vasectomy, or infection, exposing sperm antigens to systemic immunity and eliciting IgG or IgA responses that correlate with oligoasthenoteratozoospermia. Cell-mediated immunity, involving T-lymphocyte responses against sperm antigens, exacerbates damage in conditions like autoimmune orchitis, though its prevalence is lower and harder to quantify than humoral ASA. High ASA levels (>50% motile sperm bound) independently predict reduced natural conception rates and necessitate over standard IVF, as antibodies hinder fertilization. Overlap exists with infectious triggers, where microbial components mimic sperm antigens, inducing cross-reactive immunity that sustains .

Endocrine and Hormonal Imbalances

Endocrine disorders account for approximately 2-5% of male infertility cases, primarily by disrupting the hypothalamic-pituitary-gonadal (HPG) axis that coordinates (GnRH), (LH), (FSH), and testosterone production essential for . Disruptions lead to , , or impaired through mechanisms such as reduced function or support for maturation. Diagnosis typically involves serum measurements of FSH, LH, testosterone, and , with imaging for pituitary lesions if indicated. Hypogonadotropic hypogonadism, a form of secondary , arises from hypothalamic or pituitary deficiencies that suppress GnRH pulsatility or secretion, resulting in low FSH and LH levels alongside reduced testosterone and impaired . Causes include congenital conditions like , acquired pituitary tumors, or infiltrative diseases such as hemochromatosis, which collectively impair fertility by halting germ cell proliferation and maturation in the seminiferous tubules. Unlike primary —characterized by testicular failure with elevated FSH and LH but low testosterone—secondary forms are often reversible via therapy, as exogenous testosterone replacement suppresses further. Prevalence in infertile men varies, but pituitary adenomas contribute in up to 10-15% of secondary cases. Hyperprolactinemia, defined as serum exceeding 15 μg/L, inhibits GnRH secretion via dopamine pathway disruption, mimicking with reduced LH, FSH, testosterone, and production. It occurs in about 2.1% of men evaluated for , often linked to prolactinomas (prevalence ~0.35%) or medications like antipsychotics, though mildly elevated levels (<25 μg/L) rarely impair fertility directly. Treatment with dopamine agonists such as cabergoline normalizes and restores spermatogenesis in responsive cases, with semen parameters improving within 3-6 months. Acute elevations suppress testosterone via adrenal glucocorticoid induction, underscoring a direct causal link to fertility decline. Thyroid dysfunction, though less common than gonadal axis issues, affects semen quality through altered metabolic and hormonal signaling; hypothyroidism reduces semen volume, sperm count, and progressive motility by impairing Leydig and Sertoli cell function, while hyperthyroidism may cause oligospermia via oxidative stress on germ cells. Studies indicate subclinical hypothyroidism correlates with poorer sperm morphology in 10-20% of infertile men, with normalization post-levothyroxine therapy. Conversely, hyperthyroidism's fertility impact is debated but linked to elevated estradiol from thyroid hormone excess, disrupting the HPG axis. Radioactive iodine treatment for thyroid cancer further risks azoospermia, with recovery rates varying by dose and pretreatment sperm banking efficacy. Other endocrine imbalances, such as from glucocorticoid excess, suppress gonadotropins and induce testicular atrophy, while adrenal disorders like congenital adrenal hyperplasia elevate androgens that feedback-inhibit LH. These rarer etiologies necessitate comprehensive hormonal profiling to distinguish from primary gonadal defects, emphasizing causal evaluation over symptomatic correlation.

Environmental Toxins and Lifestyle Factors

Exposure to environmental toxins, particularly endocrine-disrupting chemicals (EDCs) such as phthalates and bisphenol A (BPA), has been linked to impaired semen quality in human studies, including reduced sperm concentration, motility, and increased DNA fragmentation. Phthalates, commonly found in plastics and personal care products, interfere with testosterone synthesis and androgen receptor activity, leading to testicular toxicity and diminished spermatogenesis in both animal models and epidemiological data from occupationally exposed men. BPA, a xenoestrogen used in polycarbonate plastics and epoxy resins, mimics estrogen and disrupts Leydig cell function, correlating with lower sperm counts and vitality in cohort studies of men with urinary BPA levels above 4 μg/L. Heavy metals like cadmium, accumulated through contaminated food and industrial exposure, induce oxidative stress in seminiferous tubules, resulting in apoptosis of germ cells and elevated sperm DNA damage, as evidenced by meta-analyses showing dose-dependent fertility declines in exposed populations. Pesticides and persistent organic pollutants, including organophosphates and polychlorinated biphenyls (PCBs), contribute to male infertility via bioaccumulation in adipose tissue and disruption of the hypothalamic-pituitary-gonadal axis, with longitudinal studies reporting up to 20-30% reductions in sperm motility among agricultural workers. Inhaled toxins from air pollution, such as particulate matter and volatile organic compounds, exacerbate these effects by promoting systemic inflammation and direct testicular oxidative damage, with recent reviews indicating higher infertility rates in urban males exposed to PM2.5 levels exceeding 25 μg/m³ annually. Chronic low-dose exposures predominate in modern environments, contrasting with acute high-dose scenarios, and animal data reinforce causality through histopathological evidence of Sertoli cell dysfunction and impaired blood-testis barrier integrity. Among lifestyle factors, cigarette smoking consistently impairs male fertility, with meta-analyses of over 5,000 men demonstrating 13-17% lower sperm concentrations and 10% reduced motility in smokers compared to non-smokers, attributed to nicotine-induced vasoconstriction, cadmium deposition, and reactive oxygen species damaging sperm membranes. Heavy alcohol consumption (>14 units/week) correlates with and asthenospermia via ethanol's suppression of and direct testicular toxicity, as shown in prospective studies where improved parameters within 3 months. Obesity, defined by BMI ≥30 kg/m², disrupts male reproductive function through aromatization of testosterone to in , leading to and semen volume reductions of 10-20% in affected men, though evidence for direct sperm DNA integrity effects remains mixed and requires further clarification via randomized trials. Excessive scrotal heat from prolonged laptop use on the lap or tight clothing significantly elevates scrotal temperature by 1-2°C, inhibiting as confirmed by thermographic studies showing reversible declines in production. Prolonged laptop use in this position causes substantial scrotal hyperthermia due to heat exposure and posture effects. In vitro studies indicate that electromagnetic fields from Wi-Fi may reduce sperm motility and increase DNA fragmentation, though heat is the primary factor. Poor diet low in antioxidants and high in processed foods exacerbates , while elevates , indirectly suppressing testosterone; interventions like Mediterranean diets have yielded 20-50% improvements in in observational cohorts. These factors often interact synergistically with toxins, amplifying risk through compounded endocrine and oxidative pathways.

Post-Testicular Obstructions and Other Causes

Post-testicular obstructions arise from blockages or dysfunctions in the , , ejaculatory ducts, or , impeding transport from the testes to the ejaculate despite intact . These conditions contribute to 40% of cases overall, with obstructive mechanisms accounting for up to 7-51% of azoospermic males depending on diagnostic criteria. Diagnosis typically involves imaging such as transrectal or scrotal exploration to identify sites of obstruction, often confirmed by normal testicular or high FSH levels distinguishing them from primary testicular failure. Congenital obstructions include congenital bilateral absence of the (CBAVD), present in 1-2% of infertile males and up to 6% of obstructive cases. CBAVD frequently results from in the CFTR , with over 90% of cystic fibrosis-affected males exhibiting this anomaly due to defective chloride transport disrupting ductal development. Unilateral absence or segmental of the occurs less commonly, at a of 0.5-1% in males evaluated for . Epididymal anomalies, such as or cysts, and obstructions from midline cysts or further exemplify congenital etiologies, often linked to Müllerian duct remnants. Acquired obstructions stem from inflammatory, infectious, iatrogenic, or traumatic insults. or from sexually transmitted infections like or leads to scarring and in 2-10% of post-infectious infertility cases. Iatrogenic causes include , which intentionally severs the and results in obstructive in nearly all cases unless reversed, as well as inadvertent injury during repair or surgery. Trauma, such as scrotal injury or damage, can induce vasal or strictures, while chronic contributes to distal obstructions via seminal vesicle inflammation. Beyond obstructions, ejaculatory dysfunctions constitute key post-testicular causes, including where enters the bladder due to bladder neck incompetence. This affects approximately 1% of male infertility cases, commonly arising from , alpha-adrenergic blocker medications, or . or failure of emission, often injury-related, similarly prevents antegrade delivery. Antisperm antibodies, developing post-obstruction or in 40-70% of such cases, impair and by binding to sperm surfaces, exacerbating infertility through immune-mediated . These immunological responses highlight how breaches in ductal integrity trigger systemic against sperm antigens.

Diagnosis

Medical History and Physical Assessment

The evaluation of male infertility begins with a detailed to identify potential contributing factors, including the duration of attempted conception (typically defined as 12 months of unprotected intercourse for couples under 35 years or 6 months for those over 35), coital frequency, and any history of prior pregnancies or fertility treatments. Inquiries should cover sexual function, such as , ejaculatory disorders (e.g., or ), and , as these can impair semen delivery. Past medical history includes childhood conditions like or orchitis, sexually transmitted infections (e.g., or , which may cause ), genitourinary trauma or surgeries (e.g., repair or ), and chronic illnesses such as diabetes mellitus or renal failure that could affect . Medication use, including testosterone replacement therapy (which suppresses gonadotropins and ), chemotherapy, or anabolic steroids, must be documented, as should lifestyle factors like (associated with reduced sperm concentration by up to 20% in heavy users), excessive alcohol intake (>14 units/week), (e.g., marijuana impairing ), (BMI >30 linked to lower testosterone and ), and occupational exposures to heat, pesticides, or . Family history of infertility, genetic disorders (e.g., ), or congenital anomalies is also elicited to guide potential . Physical assessment, ideally performed by a urologist or andrologist, focuses on the reproductive tract and signs of systemic disorders. A general examination evaluates body habitus for or indicators, such as reduced facial or body hair, , or eunuchoid proportions, which suggest endocrine imbalances like . The genital examination includes inspection and palpation of the for structural defects like , , or ; the for asymmetry or swelling; and bilateral assessment of the testes using a Prader to measure volume (normal range 15-30 mL per testis, with volumes <15 mL indicating atrophy and potential oligospermia). Testicular consistency is noted for firmness (softening suggests Sertoli cell-only syndrome or prior injury), while the epididymis and vas deferens are palpated for nodularity, absence (as in congenital bilateral absence of vas deferens), or cysts. Varicocele detection involves standing palpation with and without Valsalva maneuver, grading palpable dilatations as subclinical (Doppler-detected only), grade 1 (palpable only with Valsalva), grade 2 (palpable without Valsalva), or grade 3 (visible), as left-sided varicoceles occur in 15-20% of infertile men versus 5% of fertile controls and correlate with ipsilateral testicular hypotrophy. The spermatic cord is examined for masses or tenderness, and a digital rectal exam may assess prostate size or consistency if indicated for suspected obstruction or infection. This targeted approach identifies treatable causes in up to 40% of cases, informing subsequent semen analysis or hormonal testing.

Semen Analysis Protocols

Semen analysis serves as the cornerstone of male infertility evaluation, providing quantitative and qualitative assessment of ejaculated semen to identify potential defects in spermatogenesis, sperm maturation, or transport. Standardized protocols, primarily outlined in the sixth edition laboratory manual published in 2021, emphasize rigorous, evidence-based procedures to minimize variability and ensure reproducibility across laboratories. These protocols recommend performing at least two separate analyses on specimens collected 1-2 weeks apart to account for inherent biological fluctuations in semen parameters. Sample collection occurs preferably via masturbation in a private room at or near the laboratory to capture the complete ejaculate, which consists of sperm from the testes and accessory gland secretions. A period of sexual abstinence lasting 2-7 days is required, with 3 days considered optimal to standardize results while reflecting typical reproductive conditions. The specimen must be collected into a wide-mouthed, sterile, non-toxic container provided by the laboratory, labeled with patient identifiers, collection date, and time. If collection at home is necessary, transport to the laboratory must occur within 30-60 minutes, maintaining a temperature of 20-37°C to preserve sperm viability, such as by keeping the container close to the body. Incomplete collection or use of lubricants, soaps, or condoms should be documented, as these can contaminate or dilute the sample. Upon receipt, the sample undergoes macroscopic examination for volume, appearance, viscosity, and liquefaction time. Liquefaction, the process converting coagulated semen to liquid form due to enzymatic action, typically completes within 15-60 minutes at room temperature or 37°C; incomplete liquefaction after 60 minutes warrants notation and may indicate prostate dysfunction. Volume is measured via graduated pipette or by weighing (assuming density of 1 g/mL), subtracting container weight if applicable. pH is assessed within 1 hour using pH paper or meter, with values below 7.2 suggesting accessory gland issues. Microscopic evaluation follows gentle mixing to homogenize the sample without damaging sperm, using phase-contrast microscopy for motility and bright-field for other elements. All assessments occur within 1 hour of ejaculation to mitigate post-ejaculatory changes in sperm function. Laboratories must implement internal and external quality control, including daily calibration of equipment like haemocytometers and microscopes, to ensure accuracy. Sperm concentration and total number are determined using an improved Neubauer haemocytometer after dilution (e.g., 1:20 or 1:50) and counting at least 200 spermatozoa across multiple fields under phase-contrast at 200-400x magnification. Motility is classified into progressive (rapid or slow, ≥5 μm/s), non-progressive (<5 μm/s), and immotile categories, assessing at least 200 sperm in a 20 μm-deep chamber warmed to 37°C. Morphology evaluation requires staining smears (e.g., Papanicolaou) and examining at least 200 sperm at 1000x oil immersion, applying strict criteria where normal forms exhibit specific head (oval, 4.0-5.0 μm wide, 4.6-6.2 μm long), midpiece, and tail dimensions without defects. Vitality testing, via eosin-nigrosin stain or hypo-osmotic swelling, is performed if total motility is below 40%, staining at least 200 sperm to differentiate live (unstained or swollen tails) from dead. Peroxidase staining identifies leukocytes, with counts exceeding 1 million/mL indicating potential infection or inflammation. Agglutination (sperm clumping) and debris are noted qualitatively. The WHO manual provides lower reference limits as the 5th centiles from semen parameters of over 3500 men whose partners conceived within 12 months, derived from multinational studies but acknowledging data limitations such as regional variations and small sample sizes for some parameters. These limits are interpretive thresholds rather than strict fertility cutoffs, as values below them correlate with reduced conception probability but do not preclude fertility.
ParameterLower Reference Limit (5th Centile)95% Confidence Interval
Semen Volume1.4 mL1.2–1.7
Sperm Concentration15 million/mL12–18
Total Sperm Number39 million/ejaculate33–46
Total Motility40%38–44
Progressive Motility30%28–36
Normal Morphology4%3.0–4.0
Vitality54%50–63
Abnormal results prompt repeat testing and further diagnostics, such as hormonal assays or imaging, while emphasizing that semen analysis alone cannot diagnose infertility causes like genetic defects or obstructions. Adherence to these protocols reduces inter-laboratory variability, reported at 10-20% for key parameters in quality assurance programs.

Laboratory and Hormonal Evaluations

Laboratory evaluations for male infertility extend beyond semen analysis to include genetic testing and biochemical assays that identify underlying causes such as chromosomal anomalies or metabolic disruptions. Genetic testing, particularly karyotyping, is recommended for men with azoospermia or severe oligospermia (sperm concentration <5 million/mL), as it detects abnormalities like (47,XXY karyotype), which occurs in approximately 10-12% of such cases and impairs spermatogenesis due to testicular dysgenesis. Y-chromosome microdeletion analysis via polymerase chain reaction is indicated in non-obstructive azoospermia or severe oligospermia, identifying deletions in the AZF regions of the Yq arm in 5-13% of affected men, which disrupt sperm production genes and predict poor response to assisted reproduction without donor sperm. Hormonal evaluations assess the hypothalamic-pituitary-gonadal axis and are advised for all infertile men or those with abnormal semen parameters, using fasting morning serum samples to measure follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, prolactin, and estradiol. Elevated FSH (>7.6-12.4 IU/L, depending on assay) with normal or low testosterone indicates primary testicular failure, reflecting depleted spermatogonia and dysfunction, while low FSH and LH (<1.6 IU/L and <1.3 IU/L, respectively) with testosterone <300 ng/dL suggest hypogonadotropic hypogonadism from hypothalamic or pituitary defects. Normal ranges include testosterone 300-1000 ng/dL, LH 1.6-8.0 IU/L, and FSH 1.3-8.4 IU/L in fertile young men, with deviations guiding further imaging or therapy; hyperprolactinemia (>15 ng/mL) warrants pituitary evaluation due to its inhibition of release.
HormoneReference Range (Adult Males)Clinical Implication in Infertility
FSH1.3-8.4 IU/LElevated: Primary ; Normal/low with : Possible obstruction
LH1.6-8.0 IU/LLow with low testosterone: Secondary
Testosterone300-1000 ng/dLLow (<300 ng/dL): Impaired spermatogenesis; Measure morning levels
Prolactin<15 ng/mLElevated: Suppresses GnRH, treatable cause
Additional laboratory tests may include antisperm antibody assays in cases of suspected immune-mediated infertility, though their diagnostic yield is limited to 10% of non-obstructive without leukocytospermia. Per AUA/ASRM guidelines (amended 2024), these evaluations should integrate with history and semen findings, avoiding routine testing in normospermic men unless endocrine symptoms like gynecomastia or small testes are present, to optimize cost-effectiveness and diagnostic precision.

Imaging and Specialized Tests

Scrotal ultrasound is the primary imaging modality employed in evaluating male infertility, utilizing high-frequency sound waves to assess testicular anatomy, epididymis, and vascular structures. It effectively detects , which are dilated pampiniform plexus veins present in approximately 15% of the general male population but up to 40% of infertile men, potentially impairing through increased scrotal temperature and oxidative stress. Diagnostic criteria include vein diameters exceeding 3 mm with reflux during , confirmed via color Doppler, offering sensitivity and specificity over 90% compared to physical examination alone. Additionally, scrotal ultrasound identifies epididymal obstructions, cysts, or testicular tumors that may contribute to obstructive or . Transrectal ultrasound (TRUS) is indicated for suspected post-testicular obstructions, particularly in cases of low ejaculate volume (<1.5 mL), azoospermia, or oligospermia with acidic semen pH, targeting the prostate, seminal vesicles, and ejaculatory ducts. It reveals ejaculatory duct cysts, dilatations, or calcifications obstructing sperm transport, with seminal vesicle dilation (>1.5 cm) serving as a key indicator of obstruction in up to 70% of such cases. TRUS-guided aspiration can confirm obstruction by yielding sperm-rich fluid, aiding differentiation from testicular failure. This modality's resolution allows visualization of midline cysts or Wolffian duct anomalies, though it requires patient tolerance of the probe insertion. Testicular biopsy, a specialized invasive procedure, is reserved for azoospermic or severely oligospermic men to differentiate obstructive from non-obstructive and evaluate spermatogenic potential. Open or needle samples provide histological assessment: normal sperm production with maturation or hypospermatogenesis suggests non-obstructive causes amenable to retrieval for assisted reproduction, while Sertoli-cell-only syndrome or fibrosis indicates primary failure. Performed under , it retrieves viable in 30-60% of non-obstructive cases for (ICSI), though risks include (1-3%) and . Biopsy findings correlate with fertility outcomes, with focal spermatogenesis often yielding higher retrieval rates than diffuse patterns. Magnetic resonance imaging (MRI) serves as an adjunct for complex cases, such as suspected hypothalamic-pituitary lesions causing or intratesticular masses not discernible by . It offers superior soft-tissue contrast for evaluating , which associates with a 1-2% increased germ-cell tumor in infertile cohorts, or vascular anomalies. However, MRI's higher cost and limited availability restrict routine use, with guidelines recommending it only when is inconclusive.

Management

Preventive Measures and Lifestyle Interventions

Modifiable lifestyle factors play a critical role in preventing male infertility by mitigating risks to and , with empirical evidence from cohort studies and meta-analyses supporting interventions that address tobacco use, alcohol consumption, , diet, , and thermal exposure. Guidelines from professional societies emphasize counseling men on these factors during preconception evaluations and consulting a urologist or reproductive specialist for fertility concerns to optimize potential. Tobacco cessation is a intervention, as current exhibit significantly lower concentrations than never-smokers, per a of observational data showing dose-dependent declines in volume, count, , and morphology associated with use. Quitting reverses some oxidative damage to DNA, with improvements in parameters observed within months in interventional studies. Similarly, avoiding marijuana and electronic nicotine delivery systems is advised, given associations with reduced count and in user cohorts. Alcohol moderation prevents disruptions to hormonal balance and , as heavy consumption (exceeding 14 units weekly) correlates with lowered testosterone and impaired production in cross-sectional analyses of infertile men. Limiting intake to minimal levels aligns with evidence that even moderate drinking elevates sperm DNA fragmentation, whereas or low consumption preserves . Weight management through caloric restriction and exercise counters obesity's adverse effects, including reduced total count and volume documented in a 2017 of and obese men. Bariatric interventions or lifestyle programs yielding 5-10% body improve normal morphology by approximately 0.59% on average, according to fixed-effect of randomized trials. exacerbates via increased conversion and , underscoring the need for BMI maintenance below 25 kg/m² preconception. Dietary optimization enhances via intake. The Mediterranean diet is among the best-supported dietary patterns for improving male fertility and sperm motility, emphasizing fruits, vegetables, nuts, whole grains, legumes, fish, olive oil, and moderate poultry while limiting red/processed meats and processed foods. Higher adherence is linked to better sperm parameters, including progressive motility (increased by ~5-6% in meta-analyses), total motility, concentration, and count, due to high antioxidants, anti-inflammatory effects, and nutrients like omega-3s, zinc, and selenium. Other healthy patterns (e.g., DASH or prudent diets) show similar benefits, primarily from observational studies with limitations in establishing causality and evidence quality. Systematic reviews support reducing processed meats, sugary beverages, and trans fats while increasing omega-3s, as these shifts correlate with better parameters; supplementation with (500-1000 mg/day, often combined with ), (200-300 mg/day), (200 µg/day), L-carnitine (2 g/day), and (15-30 mg/day) shows mixed evidence from meta-analyses, with improvements in sperm parameters such as motility, morphology, and DNA fragmentation but inconsistent or modest effects on pregnancy and live birth rates; vitamin C is typically studied in combinations rather than isolation, with few large RCTs on high doses alone; modest benefits are observed in randomized trials for idiopathic cases, though results vary by baseline deficiency. Regular exercise without boosts reproductive outcomes, as moderate aerobic (e.g., running, swimming, cycling) and strength training (e.g., gym workouts) improve circulation, reduce overweight, boost testosterone, and enhance hormonal profiles and semen motility in meta-analyses, contrasting with sedentary lifestyles that parallel fertility declines. Aim for about 150 minutes per week of moderate-intensity activity, per public health data tying to preserved function. Avoid extreme training like marathon preparation or intense bodybuilding, which can temporarily worsen sperm quality. Avoiding scrotal preserves spermatogenic efficiency, as prolonged exposure to heat sources like saunas (>40°C for >30 minutes), hot tubs, or tight undergarments elevates testicular temperature by 1-2°C, impairing production per studies. Recommendations include loose clothing, avoiding laptop placement on the lap, and limiting , with recovery of parameters post-avoidance in affected cohorts. Stress reduction via or may indirectly support , as chronic psychological strain associates with lower in longitudinal data, though causation requires further randomized evidence. Overall, these interventions, when combined, yield synergistic effects, with comprehensive programs demonstrating up to 20-30% improvements in natural conception rates in subfertile populations.

Pharmacological and Hormonal Treatments

Pharmacological and hormonal treatments for male infertility primarily target underlying endocrine deficiencies or aim to empirically enhance in cases of idiopathic oligozoospermia or asthenospermia. These interventions are most effective in , where (GnRH) analogs, (hCG), (FSH), or human menopausal gonadotropin (hMG) stimulate testicular function, achieving in up to 80-90% of men with isolated (IHH). Combinations of hCG (to mimic and support testosterone production) and recombinant FSH have induced sperm production sufficient for assisted reproduction in 70-75% of cases, with pregnancy rates of 40-60% via intrauterine insemination or in vitro fertilization. Pulsatile GnRH therapy, administered via portable pumps, restores physiological gonadotropin pulses and yields sperm in semen for 75-80% of IHH patients, though it requires strict compliance and monitoring for ovulation-like surges. For eugonadal or mildly hypogonadal men with idiopathic infertility, selective estrogen receptor modulators (SERMs) like clomiphene citrate (CC) block hypothalamic estrogen feedback, elevating endogenous FSH and levels to boost intratesticular testosterone. A 2023 meta-analysis of randomized trials found CC significantly increased sperm concentration by 5-10 million/mL and motility by 5-10% after 3-6 months, with rates improving in 20-30% of couples, though live birth data remain limited by small sample sizes. , another SERM, shows comparable effects on parameters, with a 2024 meta-analysis reporting odds ratios of 1.5-2.0 for spontaneous in subfertile men, but quality is moderate due to heterogeneity in dosing (10-20 mg daily) and durations (3-12 months). Side effects for both include (5-10%) and visual disturbances (<2%), resolving upon discontinuation. Aromatase inhibitors (AIs) such as anastrozole (1 mg daily) or letrozole (2.5 mg daily) reduce estrogen conversion from testosterone, normalizing testosterone-to-estradiol ratios in men with elevated estradiol. A 2020 meta-analysis of 12 trials demonstrated AIs improved sperm count by 15-20 million/mL and motility by 10%, with better outcomes in obese or varicocele-associated cases, though pregnancy rates varied (10-25%) and long-term safety data are sparse beyond 6-12 months. A 2022 review confirmed efficacy in non-responders to SERMs, with meta-analytic odds for semen improvement at 2.5, but cautioned against use in hypergonadotropic hypogonadism where testicular failure precludes response. Empirical hormonal therapies in normogonadal idiopathic infertility yield inconsistent results, with a 2021 network meta-analysis ranking antioxidants (including vitamin C often combined with vitamin E) and SERMs highest for semen parameter gains such as motility, morphology, and DNA fragmentation, but overall live birth improvements <10% over placebo and inconsistent effects on pregnancy rates, underscoring the need for pretreatment hormonal profiling to avoid futile use; antioxidants show promise for sperm quality but data are not definitive for clinical outcomes, with vitamin C typically studied in combinations rather than isolation and few large RCTs on high doses alone. No pharmacological agents reliably reverse primary testicular failure, as spermatogenic stimulants fail to overcome intrinsic germ cell defects. Treatment durations typically span 3-6 months for parameter assessment, with monitoring for prostate effects or erythrocytosis, particularly with hCG regimens exceeding 1500 IU weekly. Despite parameter enhancements, many men proceed to assisted reproductive technologies, as natural conception rates remain suboptimal without addressing multifactorial causes.

Surgical Corrections

Surgical corrections for male infertility primarily address anatomical defects such as varicoceles, ductal obstructions, and ejaculatory pathway blockages, or facilitate sperm retrieval when natural ejaculation is impossible. These procedures, often microsurgical, aim to restore sperm production, transport, or accessibility for assisted reproduction. Success varies by etiology, with patency rates exceeding 90% in many reconstructive cases, though pregnancy outcomes depend on factors like partner fertility and time elapsed since onset. Varicocelectomy, the excision or ligation of dilated scrotal veins, targets varicoceles, which impair spermatogenesis via elevated testicular temperature and oxidative stress. Microsurgical subinguinal varicocelectomy yields superior outcomes, with semen parameter improvements in 60-70% of cases, including increased sperm concentration and motility, and reduced DNA fragmentation. A 2024 study reported significant post-operative enhancements in sperm count, motility, and pregnancy rates among infertile men with clinical varicoceles. Meta-analyses confirm higher spontaneous pregnancy rates (up to 40%) compared to embolization or non-microsurgical approaches, with complication rates under 1% for microsurgery. Reconstructive surgeries for post-testicular obstructions, such as vasovasostomy or following vasectomy, restore ductal continuity using microsutures. Vasovasostomy achieves sperm return to ejaculate in 95-98% of cases when performed within 10 years of vasectomy, dropping to 70-80% beyond 15 years due to antisperm antibody formation and secondary epididymal damage. Pregnancy rates average 50-60%, influenced by obstruction duration and female partner age; repeat procedures yield patency in 75% but lower overall success. , required for distal obstructions, has patency rates of 60-90% but demands advanced microsurgical expertise. Transurethral resection of ejaculatory ducts (TURED) corrects ejaculatory duct obstruction (EDO), a rare cause of low-volume azoospermia, by incising blockages under cystoscopic guidance. This procedure restores antegrade ejaculation and semen parameters in 60-80% of cases, with post-operative fertility achieved via natural conception or insemination. Complications include retrograde ejaculation (5-10%) and prostatic reflux, but long-term data affirm its efficacy for verifiable obstructions confirmed by imaging or seminal vesiculography. For non-obstructive azoospermia (NOA), sperm retrieval techniques like microdissection testicular sperm extraction (microTESE) sample focal spermatogenic areas under operating microscopy, yielding usable sperm in 40-60% of men versus 20-30% for conventional TESE. In obstructive azoospermia, less invasive percutaneous epididymal sperm aspiration (PESA) or testicular sperm aspiration (TESA) suffice, with retrieval rates over 90%. These retrieved sperm enable intracytoplasmic sperm injection (ICSI), though retrieval does not restore ejaculatory fertility. Varicocelectomy prior to microTESE in NOA with varicoceles boosts retrieval rates by 10-20%.

Assisted Reproductive Technologies

Assisted reproductive technologies (ART) address male infertility by circumventing deficits in sperm quantity, motility, or quality, enabling fertilization outside natural conception pathways. These include intrauterine insemination (IUI), conventional , and , often combined with surgical sperm retrieval for azoospermic cases. IUI involves semen processing and direct uterine placement, suitable for mild male factor infertility with total motile sperm count (TMC) thresholds of 5–10 million and inseminating motile count of 0.8–5 million per milliliter. Pregnancy rates per cycle reach 12.5% when TMC exceeds 10 million but drop to 5.2% below 1 million, with elevated miscarriage risks linked to high sperm DNA fragmentation. IUI success in mild male factor cases averages 16.9% per cycle when TMC surpasses 5 million. For moderate-to-severe oligozoospermia or failed IUI, IVF or ICSI is employed, with minimum criteria including TMC of 0.2–1 million and morphology of at least 5% normal forms. ICSI, the standard for severe male factors like azoospermia, immotile sperm, or globozoospermia, entails direct injection of a single spermatozoon into the oocyte, yielding fertilization rates of 70–80%. This bypasses natural selection, potentially transmitting paternal genetic defects, though no conclusive increase in embryo aneuploidy or adverse obstetric outcomes has been established. In non-male factor infertility, conventional IVF shows higher live birth rates per transfer (33.3%) than ICSI (26.5%), but ICSI remains essential for profound male impairments. Azoospermia necessitates surgical sperm retrieval prior to ICSI, with techniques differentiated by obstructive (OA) versus non-obstructive (NOA) etiology. For OA, percutaneous epididymal sperm aspiration (PESA) or microsurgical epididymal sperm aspiration (MESA) achieves sperm retrieval rates of 90–100%, enabling cryopreservation for future use with outcomes comparable to fresh sperm. Testicular methods like testicular sperm aspiration (TESA) or conventional TESE serve as alternatives. In NOA, microdissection TESE (micro-TESE) targets dilated tubules under magnification, attaining retrieval rates of 35–77%—higher than standard TESE (49.5%) or TESA (10–30%)—with overall success around 40–50% across studies. Post-retrieval ICSI fertilization rates approximate 75%, leading to clinical pregnancy rates of 40–50% in successful cases, though live birth delivery rates vary by maternal factors and embryo quality. Complications from retrieval include hematoma (PESA/TESE), spermatocele (PESA), or testicular atrophy (TESE), though micro-TESE minimizes tissue removal and androgen disruption. Cryopreserved retrieved sperm supports deferred ICSI cycles without compromising viability in OA. Overall ART efficacy depends on semen parameters, female partner age, and DNA integrity, with no universal superiority among advanced sperm selection adjuncts like magnetic-activated cell sorting. Donor sperm remains an option for irretrievable cases, though ethical and genetic counseling is advised.

Research Directions

Recent Advances in Diagnostics

Advances in diagnostics for male infertility have increasingly emphasized functional sperm evaluations and molecular profiling to address limitations in standard semen analysis, which often fails to predict fertility outcomes accurately. Sperm DNA fragmentation (SDF) testing, recognized as an extended examination in the World Health Organization's 6th edition laboratory manual published in 2021, assesses DNA integrity in spermatozoa and correlates with reduced success in assisted reproductive technologies, prompting recommendations for its use in cases of recurrent pregnancy loss or poor IVF outcomes. Seminal oxidative stress measurement via oxidation-reduction potential (ORP) analyzers enables diagnosis of male oxidative stress infertility (MOSI), a condition linked to up to 80% of cases in some cohorts, with evidence from 2022 studies showing varicocele repair lowers ORP levels and improves semen parameters. Genetic diagnostics have advanced through next-generation sequencing (NGS) and whole exome sequencing (WES), identifying causative variants in genes such as FANCA and TEX11 in non-obstructive azoospermia (NOA), with panels expanded to include over a dozen infertility-associated loci since 2015. The 2025 European Association of Urology guidelines incorporated exome sequencing for idiopathic severe oligozoospermia or azoospermia, reflecting its growing utility in pinpointing monogenic etiologies previously deemed idiopathic. Epigenetic biomarkers, including miRNAs like miR-192a in seminal plasma, aid in predicting spermatogenesis recovery post-varicocelectomy or testicular sperm retrieval success in NOA. Computational and microfluidic innovations enhance precision and efficiency. A 2024 machine learning model using serum hormones (FSH, LH, testosterone, estradiol) achieved an area under the curve (AUC) of 82.1% in predicting infertility risk without semen analysis, prioritizing FSH as the top feature in datasets from over 3,600 patients. Microfluidic devices, reviewed in 2025, accelerate sperm motility assessment and selection by mimicking physiological conditions, reducing processing time compared to manual methods while improving detection of viable sperm in low-count samples. Computer-assisted sperm analysis (CASA), integrated into WHO protocols, standardizes motility and morphology evaluations, minimizing inter-observer variability. Guideline updates reflect these developments; the 2024 American Urological Association/American Society for Reproductive Medicine (AUA/ASRM) revision lowered thresholds for Y-chromosome microdeletion testing in oligozoospermia and expanded pelvic MRI indications for suspected obstructions or testicular pathology, based on review of over 4,000 abstracts. These refinements prioritize evidence-based thresholds, though challenges persist in standardizing assays like SDF due to methodological variability across labs.

Emerging Therapies and Genetic Interventions

Recent advances in genetic interventions for male infertility focus primarily on preclinical models targeting spermatogonial stem cells (SSCs) and specific genetic defects. CRISPR/Cas9 technology has been employed to edit genes involved in spermatogenesis, such as those associated with azoospermia or oligozoospermia, demonstrating restoration of fertility in mouse models of genetic infertility without germline transmission of edits. For instance, CRISPR-mediated correction of mutations in SSCs has enabled functional sperm production in rodents, offering proof-of-principle for treating monogenic causes like Y-chromosome microdeletions or . A 2025 study highlighted CRISPR/Cas9's potential to address genetically linked male infertility by precisely targeting testis-enriched genes, though human applications remain limited by off-target effects and ethical concerns over heritable changes. mRNA-based therapies represent a novel non-permanent genetic approach, with lipid nanoparticle delivery restoring sperm production in mice harboring genetic defects causing infertility; this method, reported in October 2025, avoids DNA integration risks associated with viral vectors and could inform treatments for idiopathic or genetic azoospermia. Somatic gene therapy targeting testicular cells has also shown promise in animal models for non-obstructive azoospermia (NOA), enhancing spermatogenesis without altering offspring genetics. These interventions prioritize causal genetic etiologies, but clinical translation requires validation of long-term safety and efficacy, as current evidence derives from rodent studies with limited scalability to human polygenic or environmental factors. Emerging non-genetic therapies emphasize regenerative approaches, particularly stem cell transplantation to restore spermatogenic capacity in conditions like NOA or post-chemotherapy infertility. Spermatogonial stem cell (SSC) transplantation, successfully demonstrated in primates and early human trials, involves harvesting, cryopreserving, and reintroducing autologous SSCs into the testis to regenerate sperm production, with 2023-2025 reviews noting improved semen parameters in select cases. Mesenchymal stem cell (MSC) injections, including bone marrow-derived variants, have yielded phase I evidence of hormonal improvements and spermatid detection in NOA patients, though pregnancy rates remain unproven. In vitro spermatogenesis using induced pluripotent stem cells (iPSCs) has produced functional sperm in mouse models, bypassing testicular barriers, but human ethical and technical hurdles persist. Exosome therapies and organoid cultures are under investigation to modulate the testicular microenvironment, with exosomes from MSCs promoting anti-inflammatory effects and spermatogenesis in preclinical NOA models. These therapies hold potential for addressing multifactorial infertility beyond surgical or hormonal limits, yet challenges include variable engraftment rates (10-30% in animal studies), tumorigenicity risks from pluripotent cells, and the need for randomized controlled trials to confirm fertility outcomes over assisted reproduction alone. Ongoing research integrates these with diagnostics like exome sequencing to personalize interventions. Recent multicenter consortia, such as the one launched by in January 2025, are pooling data across institutions to enhance the statistical power and reproducibility of male infertility research, particularly in elucidating genetic and environmental contributors to spermatogenic impairment. This initiative addresses limitations in prior single-center studies, which often suffer from small sample sizes and selection biases that may overestimate prevalence of idiopathic cases. Investigations into temporal trends reveal conflicting patterns: a 2023 meta-regression analysis of 223 studies spanning 1973–2018 reported a 51–62% decline in mean sperm concentration globally, with steeper drops in Western countries, attributing potential drivers to endocrine-disrupting chemicals and lifestyle factors without definitive causation. Conversely, a 2025 Cleveland Clinic analysis of over 1,000 fertile U.S. men from 2017–2023 found stable sperm concentrations averaging 70–80 million/mL, challenging narratives of universal decline and highlighting geographic or methodological variances, such as inclusion of only proven fertile donors in U.S. cohorts. Ongoing longitudinal cohorts, including extensions of the U.S. National Social Life, Health, and Aging Project, are tracking age-related declines, with 2025 data confirming inverse correlations between advancing paternal age (over 40) and sperm motility/DNA fragmentation index, potentially via accumulated oxidative damage. Etiological research emphasizes multifactorial origins, with 2025 studies integrating semen microbiota profiling and metabolomics to uncover dysbiosis in idiopathic infertility, revealing elevated pathogenic bacteria (e.g., Enterococcus) and altered metabolites like lactate in 30–40% of cases, suggesting microbial-immune axes as understudied contributors. Genetic inquiries have advanced via exome sequencing protocols outlined in the 2025 European Association of Urology guidelines, identifying rare variants in spermatogenesis genes (e.g., TEX11, NR5A1) in up to 15% of azoospermic patients previously deemed idiopathic. Environmental and lifestyle factors remain focal, with cohort studies linking paternal obesity (BMI >30) to 20–25% reduced sperm quality via hypothalamic-pituitary dysregulation, while prospective trials probe phthalate exposure's role in testicular dysgenesis, though causality awaits randomized biomarker validations. These efforts prioritize over correlative associations, incorporating to disentangle confounders like reverse causation in stress-hormone pathways.

Societal Implications

The Declining Male Fertility Crisis

Observational studies spanning multiple decades reveal a marked decline in average concentration (SC) and total (TSC) among unselected men, with analyses indicating annual decreases of 1.16% for SC and 1.27% for TSC from 1973 to 2018 globally. This equates to a 51.6% reduction in SC in Western countries and 26.3% elsewhere during the period, accelerating post-2000 to 2.64% per year overall, based on data from over 100 studies involving samples from 53 countries. Parallel trends in reduced and morphology have been reported, pushing more men below thresholds (e.g., SC <15 million/ml), which correlate with impaired . These patterns extend beyond Western populations, challenging earlier notions of regional specificity and pointing to pervasive influences on . The trajectory raises alarms for a male fertility crisis, as sustained declines could render median SC subfertile by 2045 in high-income regions, compounding observed drops in total rates from 2.5 children per in 2000 to below replacement levels in many nations by 2023. Male factors contribute to 40-50% of cases among couples, with 1 in 20 men now exhibiting or worse, up from prior baselines, and driving a 5-10% annual rise in assisted demands. Temporal correlations link these shifts to rising incidence, genital malformations, and overall reproductive disorders, suggesting systemic disruptions in male production that threaten population sustainability absent interventions. Debates persist, with select cohorts of fertile U.S. men showing stable SC from 2015-2022, potentially reflecting improved diagnostics, exclusion of infertile subjects, or localized reversals amid broader trends. Nonetheless, unselected population data affirm the decline's robustness, attributable less to methodological artifacts than to modifiable drivers like endocrine-disrupting chemicals (e.g., mimicking and impairing function), obesity-induced hypothalamic-pituitary dysregulation, and sedentary lifestyles elevating on germ cells. Delayed paternity, with average male age at conception rising 3-5 years since 1970, further exacerbates age-related DNA fragmentation. Empirical associations, rather than mere correlations, underscore urgency for causal elucidation through longitudinal cohorts tracking exposure-response.

Public Health Responses and Controversies

Public health responses to male infertility have primarily focused on diagnostic standardization, risk factor mitigation, and integration with broader reproductive health monitoring. The defines as the failure to achieve after 12 months of regular unprotected intercourse and emphasizes for male evaluation, with its 2021 laboratory manual providing protocols for assessing parameters to guide clinical decisions. In the United States, the Centers for Disease Control and Prevention (CDC) outlined a National Public Health Action Plan in 2016 for detection, prevention, and treatment, recommending surveillance of semen quality alongside metrics like time-to- and advocating lifestyle interventions such as weight management and avoidance of toxins. Professional guidelines from bodies like the American Urological Association (AUA) and American Society for Reproductive Medicine (ASRM), updated in 2024, stress comprehensive male evaluation including history, physical exam, and hormonal testing, while prioritizing treatable causes like repair over unproven therapies. Efforts to address modifiable risks include public education on lifestyle factors, though implementation remains fragmented. The European Association of Urology (EAU) guidelines recommend assessing behavioral risks such as , , and occupational exposures during infertility workups, with evidence linking these to reduced and count. Population-level monitoring has documented a global rise in male burden, with age-standardized prevalence rates increasing from 1990 to 2019, prompting calls for enhanced surveillance in high-burden regions. However, few governments have enacted targeted policies; instead, responses emphasize clinical guidelines over widespread screening or environmental regulations, despite evidence tying male to systemic health issues like metabolic disorders. Controversies center on the scale of declining male fertility, its causes, and the adequacy of responses. Meta-analyses report sperm concentrations halving in Western men from 1973 to 2018, attributed partly to endocrine-disrupting chemicals in plastics and , fueling demands for regulatory action like curbing , yet counter-studies in fertile U.S. cohorts show stability, questioning methodological biases in global data. Public awareness gaps exacerbate debates, with surveys indicating only 51% of men recognize key infertility risks and 67% identifying testosterone therapy's harms, potentially understating the issue amid low prioritization in health campaigns. Further contention arises over etiological emphasis, with some experts viewing male infertility as a sentinel for broader health crises like cancer and , while others attribute declines mainly to over environmental toxins, amid critiques of institutional reluctance to pursue causal links due to economic interests in consumer products. inaction persists despite warnings of crises, as seen in limited government interventions beyond guidelines, contrasting with vocal advocacy for urgent research into persistent declines observed in diverse populations. These debates highlight tensions between empirical trends and , with male factors implicated in 30-50% of infertility cases yet often overshadowed in public discourse.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK562258/
  2. https://pubmed.ncbi.nlm.nih.gov/29555319/
  3. https://www.nichd.nih.gov/health/topics/menshealth/conditioninfo/infertility
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC10631182/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC11216957/
  6. https://www.auajournals.org/doi/10.1097/JU.0000000000004180
  7. https://pubmed.ncbi.nlm.nih.gov/40507691/
  8. https://www.auanet.org/meetings-and-education/for-medical-students/medical-students-curriculum/male-infertility
  9. https://pubmed.ncbi.nlm.nih.gov/32965929/
  10. https://my.clevelandclinic.org/health/diseases/17201-male-infertility
  11. https://www.mayoclinic.org/diseases-conditions/male-infertility/symptoms-causes/syc-20374773
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC4424520/
  13. https://pubmed.ncbi.nlm.nih.gov/39752330/
  14. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1506229/full
  15. https://www.who.int/news-room/fact-sheets/detail/infertility
  16. https://www.hopkinsmedicine.org/health/conditions-and-diseases/male-infertility
  17. https://www.ncbi.nlm.nih.gov/books/NBK553142/
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC4698398/
  19. https://pmc.ncbi.nlm.nih.gov/articles/PMC10140312/
  20. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00763/full
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC4043871/
  22. https://www.mdpi.com/2218-273X/15/4/500
  23. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2019.00341/full
  24. https://academic.oup.com/hropen/article/2025/3/hoaf040/8185546
  25. https://journals.lww.com/10.4103/aja202550
  26. https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-16793-3
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC12170198/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC12443578/
  29. https://weekly.chinacdc.cn/en/article/doi/10.46234/ccdcw2024.155
  30. https://www.sciencedirect.com/science/article/pii/S2405844024163190
  31. https://tau.amegroups.org/article/view/138718/html
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC10914128/
  33. https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2025.1603916/full
  34. https://www.mdpi.com/1424-8247/15/5/519
  35. https://academic.oup.com/humrep/article/39/11/2491/7750558
  36. https://academic.oup.com/humupd/article/29/2/157/6824414
  37. https://pubmed.ncbi.nlm.nih.gov/36377604/
  38. https://www.nature.com/articles/s41585-022-00626-w
  39. https://www.mdpi.com/2079-7737/12/1/70
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC10371917/
  41. https://www.sciencedirect.com/science/article/pii/S0015028224019538
  42. https://www.manchester.ac.uk/about/news/no-evidence-sperm-counts-are-dropping-researchers-find/
  43. https://www.nytimes.com/2021/06/04/health/sperm-fertility-reproduction-crisis.html
  44. https://www.scientificamerican.com/article/are-sperm-counts-really-declining/
  45. https://academic.oup.com/humrep/article/32/12/2574/4523952
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC8527069/
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC6168324/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC8039600/
  49. https://academic.oup.com/humupd/article/18/6/703/627351
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC7008178/
  51. https://www.sciencedirect.com/science/article/pii/S0015028217304958
  52. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.729539/full
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC10886418/
  54. https://wjmh.org/DOIx.php?id=10.5534/wjmh.250004
  55. https://www.sciencedirect.com/science/article/abs/pii/S1472648322004898
  56. https://www.ncbi.nlm.nih.gov/books/NBK470270/
  57. https://www.eshre.eu/-/media/sitecore-files/SIGs/Surgery/Treviso-2010/Amer.pdf
  58. https://www.mdpi.com/2073-4425/12/12/1894
  59. https://medlineplus.gov/download/genetics/condition/congenital-bilateral-absence-of-the-vas-deferens.pdf
  60. https://pmc.ncbi.nlm.nih.gov/articles/PMC8873976/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC7110320/
  62. https://www.sciencedirect.com/science/article/pii/S0015028220306130
  63. https://www.tandfonline.com/doi/full/10.1080/19396368.2025.2548492?src=exp-la
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC6016649/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC9580820/
  66. https://virologyj.biomedcentral.com/articles/10.1186/s12985-024-02431-w
  67. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.727812/full
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC9268217/
  69. https://onlinelibrary.wiley.com/doi/10.1111/and.13743
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC5470348/
  71. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1139450/full
  72. https://academic.oup.com/humupd/article/24/4/416/4965836
  73. https://pubmed.ncbi.nlm.nih.gov/34338216/
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC9253805/
  75. https://pubmed.ncbi.nlm.nih.gov/35367058/
  76. https://journals.lww.com/ajandrology/fulltext/2019/21050/success_rates_of_in_vitro_fertilization_versus.8.aspx
  77. https://pubmed.ncbi.nlm.nih.gov/40075794/
  78. https://pmc.ncbi.nlm.nih.gov/articles/PMC8779600/
  79. https://pubmed.ncbi.nlm.nih.gov/12580560/
  80. https://www.ncbi.nlm.nih.gov/books/NBK532933/
  81. https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-hypogonadism
  82. https://www.uptodate.com/contents/induction-of-fertility-in-males-with-secondary-hypogonadism
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC5922222/
  84. https://www.sciencedirect.com/science/article/abs/pii/S0090429521002612
  85. https://onlinelibrary.wiley.com/doi/10.1155/2009/687259
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC3826086/
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC9829629/
  88. https://journals.lww.com/apjr/fulltext/2019/08050/thyroid_hormones_in_male_reproduction_and.4.aspx
  89. https://www.tandfonline.com/doi/full/10.1080/13685538.2024.2310303
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC6043754/
  91. https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2023.1232646/full
  92. https://www.sciencedirect.com/science/article/pii/S001502822301926X
  93. https://www.sciencedirect.com/science/article/pii/S0147651324016993
  94. https://enveurope.springeropen.com/articles/10.1186/s12302-021-00585-w
  95. https://www.sciencedirect.com/science/article/pii/S0147651324012545
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC7807371/
  97. https://www.mdpi.com/1422-0067/26/6/2797
  98. https://pmc.ncbi.nlm.nih.gov/articles/PMC10273357/
  99. https://www.sciencedirect.com/science/article/abs/pii/S1521693423001013
  100. https://www.ncbi.nlm.nih.gov/books/NBK576379/
  101. https://pubmed.ncbi.nlm.nih.gov/15591087/
  102. https://www.fertstert.org/article/s0015-0282(11)02678-1/fulltext
  103. https://www.frontiersin.org/journals/reproductive-health/articles/10.3389/frph.2025.1520938/full
  104. https://www.tandfonline.com/doi/full/10.1080/20905998.2024.2421626
  105. https://www.ncbi.nlm.nih.gov/books/NBK578191/
  106. https://pmc.ncbi.nlm.nih.gov/articles/PMC4537331/
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC5745269/
  108. https://link.springer.com/article/10.1007/s00439-020-02122-w
  109. https://www.health.harvard.edu/a_to_z/retrograde-ejaculation-a-to-z
  110. https://pmc.ncbi.nlm.nih.gov/articles/PMC11941111/
  111. https://www.auanet.org/guidelines-and-quality/guidelines/male-infertility
  112. https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-infertility
  113. https://emedicine.medscape.com/article/436829-clinical
  114. https://www.asrm.org/practice-guidance/practice-committee-documents/diagnosis-and-treatment-of-infertility-in-men-auaasrm-guideline-part-i-2020/
  115. https://www.mayoclinic.org/diseases-conditions/male-infertility/diagnosis-treatment/drc-20374780
  116. https://www.who.int/publications/i/item/9789240030787
  117. https://www.ncbi.nlm.nih.gov/books/NBK564369/
  118. https://pmc.ncbi.nlm.nih.gov/articles/PMC10929669/
  119. https://pmc.ncbi.nlm.nih.gov/articles/PMC8039607/
  120. https://ltd.aruplab.com/Tests/Pub/2001778
  121. https://www.maleinfertilityguide.com/hormone-testing-and-interpretation
  122. https://academic.oup.com/jcem/article/90/11/5928/2838394
  123. https://www.merckmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism
  124. https://pmc.ncbi.nlm.nih.gov/articles/PMC3746399/
  125. https://pubmed.ncbi.nlm.nih.gov/1580037/
  126. https://pubmed.ncbi.nlm.nih.gov/7484587/
  127. https://pmc.ncbi.nlm.nih.gov/articles/PMC3735160/
  128. https://www.uptodate.com/contents/approach-to-the-male-with-infertility
  129. https://www.asrm.org/practice-guidance/practice-committee-documents/optimizing-natural-fertility-a-committee-opinion-2021/
  130. https://rbej.biomedcentral.com/articles/10.1186/s12958-018-0320-7
  131. https://www.mdpi.com/2079-9721/12/9/209
  132. https://www.asrm.org/practice-guidance/practice-committee-documents/tobacco-or-marijuana-use/
  133. https://pmc.ncbi.nlm.nih.gov/articles/PMC12308875/
  134. https://academic.oup.com/humupd/advance-article/doi/10.1093/humupd/dmaf025/8279592
  135. https://pmc.ncbi.nlm.nih.gov/articles/PMC3521747/
  136. https://www.sciencedirect.com/science/article/abs/pii/S030121152400530X
  137. https://pmc.ncbi.nlm.nih.gov/articles/PMC10902424/
  138. https://academic.oup.com/humupd/article/30/3/243/7571335
  139. https://www.mdpi.com/2674-0311/1/3/16
  140. https://www.sciencedirect.com/science/article/pii/S0015028223019350
  141. https://pmc.ncbi.nlm.nih.gov/articles/PMC11166609/
  142. https://pmc.ncbi.nlm.nih.gov/articles/PMC12308861/
  143. https://rbej.biomedcentral.com/articles/10.1186/s12958-018-0436-9
  144. https://pmc.ncbi.nlm.nih.gov/articles/PMC6087845/
  145. https://www.ncbi.nlm.nih.gov/books/NBK279160/
  146. https://onlinelibrary.wiley.com/doi/10.1111/andr.13388
  147. https://www.sciencedirect.com/science/article/pii/S2214388224001139
  148. https://pubmed.ncbi.nlm.nih.gov/36680549/
  149. https://pubmed.ncbi.nlm.nih.gov/31621654/
  150. https://onlinelibrary.wiley.com/doi/10.1111/andr.13185
  151. https://pubmed.ncbi.nlm.nih.gov/34483894/
  152. https://pmc.ncbi.nlm.nih.gov/articles/PMC9139678/
  153. https://pmc.ncbi.nlm.nih.gov/articles/PMC4708300/
  154. https://pmc.ncbi.nlm.nih.gov/articles/PMC8415454/
  155. https://pmc.ncbi.nlm.nih.gov/articles/PMC3735154/
  156. https://www.sciencedirect.com/science/article/pii/S0015028219300123
  157. https://pmc.ncbi.nlm.nih.gov/articles/PMC4999483/
  158. https://academic.oup.com/humrep/article/39/Supplement_1/deae108.329/7703656
  159. https://pmc.ncbi.nlm.nih.gov/articles/PMC2658802/
  160. https://www.mayoclinic.org/tests-procedures/vasectomy-reversal/about/pac-20384537
  161. https://pmc.ncbi.nlm.nih.gov/articles/PMC3521749/
  162. https://www.sciencedirect.com/science/article/pii/S0015028219300056
  163. https://www.hopkinsmedicine.org/health/conditions-and-diseases/ejaculatory-duct-obstruction
  164. https://pmc.ncbi.nlm.nih.gov/articles/PMC3735145/
  165. https://pmc.ncbi.nlm.nih.gov/articles/PMC3114571/
  166. https://pmc.ncbi.nlm.nih.gov/articles/PMC10185595/
  167. https://webmd.com/infertility-and-reproduction/what-is-iui-success
  168. https://www.nature.com/articles/s41591-025-03621-x
  169. https://pmc.ncbi.nlm.nih.gov/articles/PMC3583154/
  170. https://pmc.ncbi.nlm.nih.gov/articles/PMC8548745/
  171. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.893679/full
  172. https://wjmh.org/DOIx.php?id=10.5534/wjmh.230232
  173. https://www.europeanurology.com/article/S0302-2838%2825%2900148-4/pdf
  174. https://www.nature.com/articles/s41598-024-67910-0
  175. https://advanced.onlinelibrary.wiley.com/doi/10.1002/admt.202401520
  176. https://pmc.ncbi.nlm.nih.gov/articles/PMC11286598/
  177. https://pmc.ncbi.nlm.nih.gov/articles/PMC9223233/
  178. https://pubmed.ncbi.nlm.nih.gov/40897994/
  179. https://www.nature.com/articles/cr2014160
  180. https://www.drugtargetreview.com/news/189727/new-mrna-therapy-could-inform-future-male-infertility-treatments/
  181. https://inventions.pitt.edu/technologies/gene-therapy-for--04279
  182. https://prolistem.com/gene-therapy-for-azoospermia-treatment/
  183. https://link.springer.com/article/10.1007/s12015-023-10577-3
  184. https://www.fertstert.org/article/S0015-0282%2825%2900433-9/pdf
  185. https://www.sciencedirect.com/science/article/pii/S0015028225004339
  186. https://www.mensreproductivehealth.com/post/the-future-of-male-fertility-stem-cells-and-exosomes-for-non-obstructive-azoospermia
  187. https://pubmed.ncbi.nlm.nih.gov/37440145/
  188. https://consultqd.clevelandclinic.org/consortium-aims-to-advance-science-around-male-infertility
  189. https://consultqd.clevelandclinic.org/no-cause-for-panic-as-sperm-counts-found-to-be-steady
  190. https://www.urotoday.com/mens-health/male-infertility.html
  191. https://pmc.ncbi.nlm.nih.gov/articles/PMC11751997/
  192. https://pmc.ncbi.nlm.nih.gov/articles/PMC10890002/
  193. https://pmc.ncbi.nlm.nih.gov/articles/PMC6877781/
  194. https://onlinelibrary.wiley.com/doi/10.1111/andr.12673
  195. https://www.cdc.gov/reproductive-health/media/pdfs/infertility/DRH-NAP-Final-508.pdf
  196. https://www.sciencedirect.com/science/article/pii/S0015028218318247
  197. https://journalistsresource.org/environment/sperm-count-falling-developed-world/
  198. https://www.theguardian.com/world/2025/aug/19/urgent-action-needed-plastic-additives-sperm-count-decline-experts-warn
  199. https://pmc.ncbi.nlm.nih.gov/articles/PMC11833537/
  200. https://progyny.com/blog/fertility-in-the-workplace/debunking-mens-health-and-fertility-myths-by-a-reproductive-urologist/
  201. https://www.mdpi.com/2077-0383/13/18/5559
  202. https://pursuit.unimelb.edu.au/articles/male-infertility-may-be-the-world-s-canary-down-a-coal-mine
  203. https://www.theguardian.com/commentisfree/2024/mar/12/men-fertility-falling-sperm-counts-conceive-problem
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