Male Infertility: Causes

Pathogenesis (development of disease)

The pathogenesis of male infertility is still partly unexplained. Essentially, a disturbance of spermatogenesis (spermatogenesis), due to genetic, organic, disease-related as well as exogenous factors (see below) is the cause of the disease.

Etiology (causes)

Biographic causes

  • Genetic burden
    • Disruption of spermatogenesis
      • Azoospermia (complete absence of spermatozoa in the ejaculate) in Klinefelter syndrome (prevalence (disease frequency) of approximately 1: 500; genetic disease with mostly sporadic inheritance: numerical chromosomal aberration (aneuploidy) of the sex chromosomes (gonosomal anomaly), which occurs only in boys or Males occurs; in the majority of cases characterized by a supernumerary X chromosome (47, XXY); clinical picture: large stature and testicular hypoplasia (small testis), caused by hypogonadotropic hypogonadism (gonadal hypofunction); usually spontaneous onset of puberty, but poor pubertal progress).
      • Azoospermia or severe oligozoospermia (< 20 million spermatozoa per milliliter) due to the occurrence of three different microdeletions on the long arm of the Y chromosome (AZFa, AZFb and AZFc/AZF = azoospermia factor; prevalence of AZF deletions is up to 1% among infertile males)
      • Azoospermia or meiosarrest due to mutations of the TEX11 gene.
      • Partial androgen resistance (synonyms: Partial androgen insensitivity syndrome, PAIS; Reifenstein syndrome) – genetic disorder with X-linked recessive inheritance in which the male androgen receptor functions inadequately; individual is genetically a male (XY sex chromosomes), the sex organs are male differentiated and androgens are also produced; the site of action of these hormones, the androgen receptor, functions inadequately or not at all; effects depend on the degree of androgen resistance: they range from gynecomastia, hypospadias (congenital anomaly of the urethra; this does not end at the tip of the glans but, depending on the severity of the degree, at the underside of the penis), micropenis (small penis), azoospermia (absence of spermatozoa in the semen) or/and cryptorchidism (undescended testis) or inguinal testis, to testicular feminization, i.e. i.e. the formation of male sexual characteristics (penis, hair type, etc.) is completely absent, the individuals grow up as girls
    • Anatomical factors
      • Obstruction (narrowing or occlusion) of the vas deferens: the so-called CBAVD (congenital bilateral aplasia of the vas deferens/congenital bilateral absence of the vas deferens) is caused by mutations in the CFTR gene and is a genital form or minimal variant of cystic fibrosis (synonym: cystic fibrosis, ZF).
    • Hormonal factors
      • Congenital hypogonadotropic hypogonadism (isolated [IHH]
      • Kallmann syndrome (synonym: olfactogenital syndrome) – genetic disorder that can occur sporadically and be inherited in an autosomal dominant, autosomal recessive, and X-linked recessive manner; symptom complex of hypo- or Anosmia (decreased to absent sense of smell) in conjunction with testicular or ovarian hypoplasia (defective development of the testis or ovaries, respectively); prevalence (disease frequency) in males 1: 10,000 and in females 1: 50,000.
  • Ageing – decrease in natural fertility due to aging – starting slowly from the age of 40:
    • Spermatozoa density (sperm density) ↓
    • Motility (mobility) of spermatozoa ↓
    • Number of abnormal spermatozoa ↑
    • Chromosomal changes ↑

Behavioral causes

  • Nutrition
    • Malnutrition – diet not complete, low in vital substances* ; too high intake of saturated fatty acids, contained in sweets, snacks, ready-made mayonnaises, ready-made dressings, ready-made meals, fried foods, breaded foods.
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol* ,
    • Coffee, black tea
    • Tobacco (smoking)* *
  • Drug use
    • Cannabis (hashish and marijuana)1+2
    • Morphine2
    • Opiates2 – strong-acting painkillers such as morphine.
  • Physical activity
    • Excessive sports
    • Heavy physical labor
  • Psycho-social situation
    • Stress
  • Overweight (BMI ≥ 25; obesity).
    • Men with severe obesity are at increased risk for decreased testicular activity compared with normal-weight men; obesity promotes hypogonadism (underactivity of the gonads); however, obesity had no effect on sperm production-except for an increased DNA fragmentation index in the group of metabolically unhealthy obese men.
    • 10 kg overweight increase the risk of infertility by 10%.
  • Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – there is a high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)); increased abdominal fat leads to a decrease in free (biologically active) testosterone When measuring waist circumference according to the guideline of the International Diabetes Federation (IDF, 2005), the following standard values apply:
    • Men < 94 cm

    The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men.

  • Underweight

1Oligozoospermia (< 20 million spermatozoa per milliliter) or impaired spermatogenesis (spermatogenesis) 2Diminished testosterone production.

* Alcohol consumptionAlcohol consumption can impair male and female fertility: sex hormones can no longer be broken down appropriately due to alcohol-induced liver damage, leading to hormonal disruption at the hypothalamus (pituitary) level, i.e. at the level of the diencephalon and pituitary gland.Increased alcohol consumption can thus lead to poorer sperm quality: Sperm cell density is reduced and the proportion of malformed sperm cells increases. Furthermore, increased alcohol consumption leads to impaired libido, i.e. sexual desire.By the way: high alcohol consumption – man > 60 g/day; woman > 40 g/day – high alcohol concentrations have been shown to lead to brain atrophy – sperm and egg cells are damaged even at much lower alcohol concentrations! * * Tobacco consumptionMale: Smoking can lead to the restriction of sperm motility and thus reduce the chances of fertilization. Furthermore, it has been shown that histones and protamines (responsible for the packaging and stability of DNA genetic information in sperm) are present in smokers in a significantly reduced concentration than in non-smokers. This can lead to no or incomplete fertilization of the oocyte (egg) and thus to subfertility. Hormonal disorders (rare)

  • Hypothalamic-pituitary disorders (hormonal disorders) as a cause of impaired spermatogenesis (spermatogenesis) are rare:
    • Primary hypogonadism
    • Secondary hypogonadism: low gonadotropin levels, such as due to pituitary adenoma or hypothalamic tumor.
    • Hyperprolactinemia (elevation of prolactin levels in the blood).
    • Genetic causes: Microdeletions on the Y chromosome with subsequent azoospermia (lack of sperm) or oligospermia (decreased sperm density), such as Klinefelter syndrome.
    • Exclude, among other things, disorders of the thyroid gland and adrenocortical tumors.

Organic (genital) causes

  • Testicular damage (testicular damage)
    • Impaired spermatogenesis (spermatogenesis) – due to a genetic abnormality (eg, Klinefelter syndrome, deletions of the Y chromosome), among others).
    • Testicular hypoplasia – underdevelopment of testicular tissue.
    • Testicular injuries (eg, Zust. n. testicular torsion).
    • Maldescensus testis (cryptorchidism, undescended testis).
    • Mumps orchitis (mumps-related testicular inflammation) – Mumps or “Goat Peter” runs in the majority of cases without serious complications. Therefore, mumps is considered a “harmless childhood disease” by the general population. However, as a complication in childhood occurs mumps meningitis and after puberty mumps orchitis.
    • Sexually transmitted infections (STI; Engl. Sexually Transmitted Infections).
      • Chlamydia (chlamydial infection): urethritis (inflammation of the urethra), prostatitis (inflammation of the prostate), epididymitis (next to testicular inflammation) and epididymoorchitis (inflammation of the epididymis and testis); direct damage to spermatozoa (sperm cells); alteration of the seminal ducts of the male genital tract).
      • Gonococci (gonorrhea): epididymitis, epididymoorchitis.
      • gential mycoplasma and ureaplasma; impairment of semen quality by ureaplasma urealyticum is possible.
      • Cytomegaloviruses (CMV): can potentially lead to orchitis (inflammation of the testis).
      • Hepatitis B: patients are more likely to have reduced semen parameters (including spermatozoa concentration, progressive motility, and morphology)
      • Hepatitis C: patients more often have reduced semen parameters (including ejaculate volume, motility).
      • Herpes simplex virus (HSV infection): may affect fertility through ascension.
      • HIV (HIV infection): patients more often have reduced semen parameters (including ejaculate volume, spermatozoa concentration, motility).
      • Human papilloma virus (HPV) infection: persistent HPV infection could potentially be a risk factor for reduced fertility
    • Spermatogenesis-damaging factors (stimulants; X-rays/ionizing radiation, heat; drugs, environmental toxins; general diseases – see below extragenital causes).
    • Varicocele (synonyms: varicocele testis; varicocele hernia)- varicose veins of the pampiniform plexus; usually also with testicular and epididymal depression on the affected side; clinical picture: feeling of heaviness and increasing swelling in the scrotal compartment, especially when standing;possible impairment of fertility as a result of overheating of the testisSurgical indication: varicocelectomy if, in addition to the varicocele, a reduced testis is also present. The threshold is a testicular atrophy index (TAI) of 20%, which means that one testicle is 20% smaller than the other; another factor is a volume difference of at least 2 ml between the two testicles.
  • Posttesticular disorders (including disorders of sperm transport).
    • Obstruction (congenital, incl. CBAVD; acquired); due to congenital bilateral aplasia (“nonformation”) of the ductus deferens/sperm duct (isolated or as a partial manifestation of cystic fibrosis/cystic fibrosis), after surgery for inguinal hernia (inguinal hernia) or testicular torsion (pedicle rotation of testis and epididymis with interruption of blood circulation), hydrocele (excessive accumulation of fluid in the scrotum)
    • Infections/inflammatory reactions (seminal ducts/ accessory glands), such as urethritis (urethritis), epididymitis (epididymitis), prostatitis (prostatitis) (one of the most common causes of male fertility problems; prevalence (disease frequency) approx. 8-15 %); obstructive (occlusive) azoospermia due to direct damage to the testis in the course of the above-mentioned urogenital infectionsEpididymitis leads to permanent azoospermia in 10 % of cases and to oligospermia (reduced number of sperm in the ejaculate) in 30 % of cases; in approx. 60% of cases also occurs testicular involvement (in such cases, testicular atrophy with permanent loss of spermatogenesis (spermatogenesis) is a feared complication).
    • Epididymal dysfunction
    • Immunological factors (spermatozoa autoantibodies).
  • Disorders of the sperm position
    • Emission and ejaculation disorders
    • Erectile dysfunction (ED, erectile dysfunction).
    • Hypospadias (congenital anomaly of the urethra; it does not end at the tip of the glans but, depending on the severity of the degree, at the underside of the penis)
    • Penile deformities (curvature of the penis).
    • Phimosis (narrowing of the foreskin)

Disease-related (extragenital) causes.

  • Diabetes mellitus – can lead to erectile and ejaculatory dysfunction, as well as be the cause of hypogonadism.
  • Febrile infections – for example bronchitides (inflammation of the bronchi), sinusitis (sinus infections) – can lead to disruption of spermatogenesis (spermatogenesis) via increased testicular temperature
  • Venereal diseases – gonorrhea, syphilis.
  • Pituitary tumor (tumor of the pituitary gland), prolactinoma (→ hyperprolactinemia).
  • Idiopathic infertility – in about 30% of male cases; in 15% percent of cases, the cause of infertility cannot be demonstrated in either the male or female.
  • Liver disease – can be the cause of secondary hypogonadism.
  • Renal insufficiency
  • Thyroid disease
  • Urotuberculosis – tuberculosis of the reproductive organs can lead to impaired spermatogenesis (spermatogenesis).

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

  • Folic acid deficiency (folic acid < 2 ng/ml) – men with high folate intake have a lower frequency of aneuploidy (genomic mutation, in the sense of a numerical chromosomal aberration in which single chromosomes are present in addition to the usual set of chromosomes) of spermatozoa (sperm cells)
  • On average, lower levels of testosterone and sex hormone-binding globulin (SHBG) and higher levels of estradiol in the blood in obese patients compared to non-obese, metabolically healthy individuals.

Medications

1Oligozoospermia (< 20 million spermatozoa per milliliter) or impaired spermatogenesis (spermatogenesis)2Ejaculatory disorders including decreased ejaculate volume3Diminished testosterone productionDrugs that can cause erectile dysfunction can be found under the disease “Erectile Dysfunction (ED) or Erectile Dysfunction”. X-rays

Surgeries

Environmental pollution – intoxications (poisonings).

  • Ionizing rays
  • Electromagnetic fields: Microwave radiation (radar station)
  • Overheating of the testicles – work at the blast furnace, bakery, frequent visits to the sauna; heated seats in the car: long and frequent driving with heated car seats can reduce the ability to conceive. Sperm become fewer in number (oligozoospermia), slower (asthenozoospermia) and are more often malformed (teratozoospermia) [oligo-astheno-teratozoospermia, OAT syndrome].
  • Air pollutants: particulate matter – particulate matter (PM2.5) in the air; increase in particulate matter concentration by 5 µg/m3 each time.
    • Decrease in sperm with normal shape and size by 1.29 percent
    • Proportion of sperm in the lowest tenth of sperm morphology increased by 26 percent
    • Slight increase in sperm concentration
  • Environmental toxins (occupational substances, environmental chemicals):
    • Bisphenol A (BPA); also the substitutes bisphenol F and S (BPF/BPS) interfere as endocrine disruptors (xenohormones) in the hormonal balance of living organisms
    • Organochlorines (e.g. dichlorodiphenyltrichloroethane (DDT), dioxins, polychlorinated biphenyls* , PCBs).
    • Solvents (e.g. glycol ether; carbon disulfide).
    • Non-ionic surfactants (e.g. alkyl phenols).
    • Pesticides, herbicides (e.g. dibromochloropropane (DBCP), ethylene dibromide).
    • Phthalates* (mainly as plasticizers for soft PVC).
    • Heavy metals (lead, mercury compounds).
    • Sunscreens such as 4-methylbenzylidene camphor (4-MBC), plastic plasticizer di-n-butyl phthalate (DnBP), the antibacterial triclosan (e.g., in toothpaste and cosmetics).

* belong to the endocrine disruptors (synonym: xenohormones), which even in the smallest amounts can damage health by altering the hormonal system. Before the start of therapeutic measures – such as artificial insemination, also called in vitro fertilization (IVF) – is required in any case – in the sense of a holistic reproductive medical diagnostics – a health check for the man including a vital substance analysis.