Idiopathic azoospermia is where there is no known cause of the condition. It may be a result of multiple risk factors, such as age and weight. For example, a review in 2013 came to the result that oligospermia and azoospermia are significantly associated with being overweight (odds ratio 1.1), obese (odds ratio 1.3) and morbidly obese (odds ratio 2.0), but the cause of this is unknown. The review found no significant relation between oligospermia and being underweight.

Nuclear receptor subfamily 5 group A member 1 (NR5A1), also known as SF1 or Ad4BP (MIM 184757), is located on the long arm of chromosome 9 (9q33.3). The NR5A1 is an orphan nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase enzyme family. This receptor is a pivotal transcriptional regulator of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation and also plays a crucial role in adrenal gland formation in both sexes. NR5A1 regulates the mullerian inhibitory substance by binding to a conserved upstream regulatory element and directly participates in the process of mammalian sex determination through mullerian duct regression. Targeted disruption of NR5A1 (Ftzf1) in mice results in gonadal and adrenal agenesis, persistence of Mullerian structures and abnormalities of the hypothalamus and pituitary gonadotropes. Heterozygous animals demonstrate a milder phenotype including an impaired adrenal stress response and reduced testicular size. In humans, NR5A1 mutations were first described in patients with 46, XY karyotype and disorders of sex development (DSD), Mullerian structures and primary adrenal failure (MIM 612965). After that, heterozygous NR5A1 mutations were described in seven patients showing 46, XY karyotype and ambiguous genitalia, gonadal dysgenesis, but no adrenal insufficiency. Since then, studies have confirmed that mutations in NR5A1 in patients with 46, XY karyotype cause severe underandrogenisation, but no adrenal insufficiency, establishing dynamic and dosage-dependent actions for NR5A1. Subsequent studies revealed that NR5A1 heterozygous mutations cause primary ovarian insufficiency (MIM 612964).

About 10–15% of human couples are infertile, unable to conceive. In approximately in half of these cases, the underlying cause is related to the male. The underlying causative factors in the male infertility can be attributed to environmental toxins, systemic disorders such as, hypothalamic–pituitary disease, testicular cancers and germ-cell aplasia. Genetic factors including aneuploidies and single-gene mutations are also contributed to the male infertility. Patients suffering from nonobstructive azoospermia or oligozoospermia show microdeletions in the long arm of the Y chromosome and/or chromosomal abnormalities, each with the respective frequency of 9.7% and 13%. A large percentage of human male infertility is estimated to be caused by mutations in genes involved in primary or secondary spermatogenesis and sperm quality and function. Single-gene defects are the focus of most research carried out in this field.

NR5A1 mutations are associated with male infertility, suggesting the possibility that these mutations cause the infertility. However, it is possible that these mutations individually have no major effect and only contribute to the male infertility by collaboration with other contributors such as environmental factors and other genomics variants. Vice versa, existence of the other alleles could reduce the phenotypic effects of impaired NR5A1 proteins and attenuate the expression of abnormal phenotypes and manifest male infertility solely.

Genetic factors can cause pretesticular, testicular, and posttesticular azoospermia (or oligospermia) and include the following situations: The frequency of chromosomal abnormalities is inversely proportional to the semen count, thus males with azoospermia are at risk to have a 10–15% (other sources citing 15–20% incidence) abnormalities on karyotyping versus about <1 % in the fertile male population.

Pretesticular azoospermia may be caused by congential hypopituitarism, Kallmann syndrome, Prader-Willi syndrome and other genetic conditions that lead to GnRH or gonadotropin deficiency.

Testicular azoospermia is seen in Klinefelter syndrome(XXY) and the XX male syndrome. In addition, 13% of men with azoospermia have a defective spermatogenesis that is linked to defects of the Y chromosome. Such defects tend to be de novo micro-deletions and affect usually the long arm of the chromosome. A section of the long arm of the Y chromosome has been termed Azoospermia Factor (AZF) at Yq11 and subdivided into AZFa, AZFb, AZFc and possibly more subsections. Defects in this area can lead to oligospermia or azoospermia, however, a tight genotype-phenotype correlation has not been achieved.

Spermatogenesis is defective with gene defects for the androgen receptor.

Posttesticular azoospermia can be seen with certain point mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene commonly associated with congenital vas deferens abnormalities.

Genetic counselling is indicated for men with genetic causes of azoospermia. In terms of reproduction, it needs to be considered if the genetic defect could be transmitted to the offspring.

All forms of androgen insensitivity are associated with infertility, though exceptions have been reported for both the mild and partial forms. Lifespan is not thought to be affected by AIS.

Due to its mild presentation, MAIS often goes unnoticed and untreated. Management of MAIS is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available. Treatment includes surgical correction of mild gynecomastia, minor hypospadias repair, and testosterone supplementation. Supraphysiological doses of testosterone have been shown to correct diminished secondary sexual characteristics in men with MAIS, as well as to reverse infertility due to low sperm count. As is the case with PAIS, men with MAIS will experience side effects from androgen therapy (such as the suppression of the hypothalamic-pituitary-gonadal axis) at a higher dosage than unaffected men. Careful monitoring is required to ensure the safety and efficacy of treatment. Regular breast and prostate examinations may be necessary due to comorbid association with breast and prostate cancers.

This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects per every 1000 males in the general population. 3.1% of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.

According to 2008 meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be related to increased age of the mother at conception, as no increase was observed in the rates of other trisomies of sex chromosomes (XXX and XYY). The National Institutes of Health; however, state that older mothers might have a slightly increased risk.

In most full-term infant boys with cryptorchidism but no other genital abnormalities, a cause cannot be found, making this a common, sporadic, unexplained (idiopathic) birth defect. A combination of genetics, maternal health, and other environmental factors may disrupt the hormones and physical changes that influence the development of the testicles.

- Severely premature infants can be born before descent of testes. Low birth weight is also a known factor.

- A contributing role of environmental chemicals called endocrine disruptors that interfere with normal fetal hormone balance has been proposed. The Mayo Clinic lists "parents' exposure to some pesticides" as a known risk factor.

- Diabetes and obesity in the mother.

- Risk factors may include exposure to regular alcohol consumption during pregnancy (5 or more drinks per week, associated with a 3x increase in cryptorchidism, when compared to non-drinking mothers. Cigarette smoking is also a known risk factor.

- Family history of undescended testicle or other problems of genital development.

- Cryptorchidism occurs at a much higher rate in a large number of congenital malformation syndromes. Among the more common are Down syndrome Prader–Willi syndrome, and Noonan syndrome.

- In vitro fertilization, use of cosmetics by the mother, and preeclampsia have also been recognized as risk factors for development of cryptorchidism.

In 2008 a study was published that investigated the possible relationship between cryptorchidism and prenatal exposure to a chemical called phthalate (DEHP) which is used in the manufacture of plastics. The researchers found a significant association between higher levels of DEHP metabolites in the pregnant mothers and several sex-related changes, including incomplete descent of the testes in their sons. According to the lead author of the study, a national survey found that 25% of U.S. women had phthalate levels similar to the levels that were found to be associated with sexual abnormalities.

A 2010 study published in the European medical journal "Human Reproduction" examined the prevalence of congenital cryptorchidism among offspring whose mothers had taken mild analgesics, primarily over-the-counter pain medications including ibuprofen (e.g. Advil) and paracetamol (acetaminophen). Combining the results from a survey of pregnant women prior to their due date in correlation with the health of their children and an "ex vivo" rat model, the study found that pregnant women who had been exposed to mild analgesics had a higher prevalence of baby boys born with congenital cryptorchidism.

New insight into the testicular descent mechanism has been hypothesized by the concept of a male programming window (MPW) derived from animal studies. According to this concept, testicular descent status is "set" during the period from 8 to 14 weeks of gestation in humans. Undescended testis is a result of disruption in androgen levels only during this programming window.

Children with XXY differ little from other children. Although they can face problems during adolescence, often emotional and behavioral, and difficulties at school, most of them can achieve full independence from their families in adulthood. Most can lead a normal, healthy life.

The results of a study carried out on 87 Australian adults with the syndrome shows that those who have had a diagnosis and appropriate treatment from a very young age had a significant benefit with respect to those who had been diagnosed in adulthood.

There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive. A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years. Later studies have reduced this estimated reduction to an average of 2.1 years. These results are still questioned data, are not absolute, and will need further testing.

Spermatogenesis arrest is a complex process of interruption in the differentiation of germinal cells of specific cellular type, which elicits an altered spermatozoa formation. Spermatogenic arrest is usually due to genetic factors resulting in irreversible azoospermia. However some cases may be consecutive to hormonal, thermic, or toxic factors and may be reversible either spontaneously or after a specific treatment.

One of the strongest arguments for early orchiopexy is reducing the risk of testicular cancer. About 1 in 500 men born with one or both testes undescended develops testicular cancer, roughly a 4 to 40 fold increased risk. The peak incidence occurs in the 3rd and 4th decades of life. The risk is higher for intra-abdominal testes and somewhat lower for inguinal testes, but even the "normally descended" testis of a man whose other testis was undescended has about a 20% higher cancer risk than those of other men.

The most common type of testicular cancer occurring in undescended testes is seminoma. It is usually treatable if caught early, so urologists often recommend that boys who had orchiopexy as infants be taught testicular self-examination, to recognize testicular masses and seek early medical care for them. Cancer developing in an intra-abdominal testis would be unlikely to be recognized before considerable growth and spread, and one of the advantages of orchiopexy is that a mass developing in a scrotal testis is far easier to recognize than an intra-abdominal mass.

It was originally felt that orchidopexy resulted in easier detection of testis cancer but did not lower the risk of actually developing cancer. However, recent data has resulted in a paradigm shift. The New England Journal of Medicine published in 2007 that orchidopexy performed before puberty resulted in a significantly reduced risk of testicular cancer than if done after puberty.

The risk of malignancy in the undescended testis is 4 to 10 times higher than that in the general population and is approximately 1 in 80 with a unilateral undescended testis and 1 in 40 to 1 in 50 for bilateral undescended testes. The peak age for this tumor is 15–45 yr. The most common tumor developing in an undescended testis is a seminoma (65%); in contrast, after orchiopexy, seminomas represent only 30% of testis tumors.

To some extent, it is possible to change testicular size. Short of direct injury or subjecting them to adverse conditions, e.g., higher temperature than they are normally accustomed to, they can be shrunk by competing against their intrinsic hormonal function through the use of externally administered steroidal hormones. Steroids taken for muscle enhancement (especially anabolic steroids) often have the undesired side effect of testicular shrinkage.

Similarly, stimulation of testicular functions via gonadotropic-like hormones may enlarge their size. Testes may shrink or atrophy during hormone replacement therapy or through chemical castration.

In all cases, the loss in testes volume corresponds with a loss of spermatogenesis.

Testicular size as a proportion of body weight varies widely. In the mammalian kingdom, there is a tendency for testicular size to correspond with multiple mates (e.g., harems, polygamy). Production of testicular output sperm and spermatic fluid is also larger in polygamous animals, possibly a spermatogenic competition for survival. The testes of the right whale are likely to be the largest of any animal, each weighing around 500 kg (1,100 lb).

Among the Hominidae, gorillas have little female promiscuity and sperm competition and the testes are small compared to body weight (0.03%). Chimpanzees have high promiscuity and large testes compared to body weight (0.3%). Human testicular size falls between these extremes (0.08%).

Testis weight also varies in seasonal breeders like deer and horses. The change is related to changes in testosterone production.

Human testicles are smaller than chimpanzee testicles but larger than gorilla testicles.

A prognosis for Alström syndrome is complicated because it widely varies. Any person that has the syndrome have different set of disorders. Permanent blindness, deafness, and Type 2 diabetes may occur. Liver and kidney failure can progressively get worse. The life expectancy is usually reduced and the patients rarely live past 50 years old.

Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically-observed disorders. Thus, Alstrom syndrome is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic kidney and liver disease, nephronophthisis, Meckel-Gruber syndrome and some forms of retinal degeneration.

Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency, and recurrent severe infections. To date about 50 cases have been reported.

Vici syndrome is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

The hypothesis of autosomal recessive inheritance of Vici syndrome was strengthened in 2002 with the clinical description of two new cases, one brother and one sister, by Chiyonobu et al.

Dyskeratosis congenita (DKC), also called Zinsser-Cole-Engman syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail , and leukoplakia of the oral mucosa, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature aging (similar to progeria). The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

Children with PSS have extremely low levels of growth hormone. These children possibly have a problem with growth hormone inhibiting hormone (GHIH) or growth hormone releasing hormone (GHRH). The children could either be unresponsive to GHRH, or too sensitive to GHIH.

Children who have PSS exhibit signs of failure to thrive. Even though they appear to be receiving adequate nutrition, they do not grow and develop normally compared to other children of their age.

An environment of constant and extreme stress causes PSS. Stress releases hormones in the body such as epinephrine and norepinephrine engage what is known as the 'fight or flight' response. The heart speeds up and the body diverts resources away from processes that are not immediately important; in PSS, the production of growth hormone (GH) is thus affected. As well as lacking growth hormone, children with PSS exhibit gastrointestinal problems due to the large amounts of epinephrine and norepinephrine, resulting in their bodies lacking proper digestion of nutrients and further affecting development.

While the cure for PSS is questionable, some studies show that placing the child affected with the disease in a foster or group home increases growth rate and socialization skills.

Bardet–Biedl syndrome (BBS) is a ciliopathic human genetic disorder that produces many effects and affects many body systems. It is characterized principally by obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure in some cases. Historically, slower mental processing has also been considered a principal symptom but is now not regarded as such.

DKC can be characterized by cutaneous pigmentation, premature graying, of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, testicular atrophy in the male carriers, and predisposition to cancer. Many of these symptoms are characteristic of geriatrics, and those carrying the more serious forms of the disease often have significantly shortened lifespans.

Psychosocial short stature (PSS) or psychosocial dwarfism, sometimes called psychogenic or stress dwarfism, or Kaspar Hauser syndrome, is a growth disorder that is observed between the ages of 2 and 15, caused by extreme emotional deprivation or stress.

The symptoms include decreased growth hormone (GH) and somatomedin secretion, very short stature, weight that is inappropriate for the height, and immature skeletal age. This disease is a progressive one, and as long as the child is left in the stressing environment, his or her cognitive abilities continue to degenerate. Though rare in the population at large, it is common in feral children and in children kept in abusive, confined conditions for extended lengths of time. It can cause the body to completely stop growing but is generally considered to be temporary; regular growth will resume when the source of stress is removed.

Affected male and carrier female dogs generally begin to show signs of the disease at two to three months of age, with proteinuria. By three to four months of age, symptoms include for affected male dogs: bodily wasting and loss of weight, proteinuria & hypoalbuminemia. Past nine months of age, hypercholesterolemia may be seen. In the final stages of the disease, at around 15 months of age for affected males, symptoms are reported as being renal failure, hearing loss and death. Since the condition is genetically dominant, diagnosis would also include analysis of the health of the sire and dam of the suspected affected progeny if available.

Ultrasonography is the primary method to evaluate autosomal recessive polycystic kidney disease, particularly in the perinatal and neonatal.

Bardet–Biedl syndrome is a pleiotropic disorder with variable expressivity and a wide range of clinical variability observed both within and between families. The main clinical features are rod–cone dystrophy, with childhood-onset visual loss preceded by night blindness; postaxial polydactyly; truncal obesity that manifests during infancy and remains problematic throughout adulthood; specific learning difficulties in some but not all individuals; male hypogenitalism and complex female genitourinary malformations; and renal dysfunction, a major cause of morbidity and mortality. There is a wide range of secondary features that are sometimes associated with BBS including