In this situation the testes are abnormal, atrophic, or absent, and sperm production severely disturbed to absent. FSH levels tend to be elevated (hypergonadotropic) as the feedback loop is interrupted (lack of feedback inhibition on FSH). The condition is seen in 49–93% of men with azoospermia. Testicular failure includes absence of failure production as well as low production and maturation arrest during the process of spermatogenesis.

Causes for testicular failure include congenital issues such as in certain genetic conditions (e.g. Klinefelter syndrome), some cases of cryptorchidism or Sertoli cell-only syndrome as well as acquired conditions by infection (orchitis), surgery (trauma, cancer), radiation, or other causes. Mast cells releasing inflammatory mediators appear to directly suppress sperm motility in a potentially reversible manner, and may be a common pathophysiological mechanism for many causes leading to inflammation. Testicular azoospermia is a kind of non-obstructive azoospermia.

Generally, men with unexplained hypergonadotropic azoospermia need to undergo a chromosomal evaluation.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a severe neurodegenerative syndrome that is associated with a particular mutation of the androgen receptor's polyglutamine tract called a trinucleotide repeat expansion. SBMA results when the length of the polyglutamine tract exceeds 40 repetitions.

Although technically a variant of MAIS, SBMA's presentation is not typical of androgen insensitivity; symptoms do not occur until adulthood and include neuromuscular defects as well as signs of androgen inaction. Neuromuscular symptoms include progressive proximal muscle weakness, atrophy, and fasciculations. Symptoms of androgen insensitivity experienced by men with SBMA are also progressive and include testicular atrophy, severe oligospermia or azoospermia, gynecomastia, and feminized skin changes despite elevated androgen levels. Disease onset, which usually affects the proximal musculature first, occurs in the third to fifth decades of life, and is often preceded by muscular cramps on exertion, tremor of the hands, and elevated muscle creatine kinase. SBMA is often misdiagnosed as amyotrophic lateral sclerosis (ALS) (also known as Lou Gehrig's disease).

The symptoms of SBMA are thought to be brought about by two simultaneous pathways involving the toxic misfolding of proteins and loss of AR functionality. The polyglutamine tract in affected pedigrees tends to increase in length over generations, a phenomenon known as "anticipation", leading to an increase in the severity of the disease as well as a decrease in the age of onset for each subsequent generation of a family affected by SBMA.

Pretesticular azoospermia is characterized by inadequate stimulation of otherwise normal testicles and genital tract. Typically, follicle-stimulating hormone (FSH) levels are low (hypogonadotropic) commensurate with inadequate stimulation of the testes to produce sperm. Examples include hypopituitarism (for various causes), hyperprolactinemia, and exogenous FSH suppression by testosterone. Chemotherapy may suppress spermatogenesis. Pretesticular azoospermia is seen in about 2% of azoospermia. Pretesticular azoospermia is a kind of non-obstructive azoospermia.

Individuals with mild (or minimal) androgen insensitivity syndrome (grade 1 on the Quigley scale) are born phenotypically male, with fully masculinized genitalia; this category of androgen insensitivity is diagnosed when the degree of androgen insensitivity in an individual with a 46,XY karyotype is great enough to impair virilization or spermatogenesis, but is not great enough to impair normal male genital development. MAIS is the mildest and least known form of androgen insensitivity syndrome.

The existence of a variant of androgen insensitivity that solely affected spermatogenesis was theoretical at first. Cases of phenotypically normal males with isolated spermatogenic defect due to AR mutation were first detected as the result of male infertility evaluations. Until then, early evidence in support of the existence of MAIS was limited to cases involving a mild defect in virilization, although some of these early cases made allowances for some degree of impairment of genital masculinization, such as hypospadias or micropenis. It is estimated that 2-3% of infertile men have AR gene mutations.

Examples of MAIS phenotypes include isolated infertility (oligospermia or azoospermia), mild gynecomastia in young adulthood, decreased secondary terminal hair, high pitched voice, or minor hypospadias repair in childhood. The external male genitalia (penis, scrotum, and urethra) are otherwise normal in individuals with MAIS. Internal genitalia, including Wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) and the prostate, is also normal, although the bitesticular volume of infertile men (both with and without MAIS) is diminished; male infertility is associated with reduced bitesticular volume, varicocele, retractile testes, low ejaculate volume, male accessory gland infections (MAGI), and mumps orchitis. The incidence of these features in infertile men with MAIS is similar to that of infertile men without MAIS. MAIS is not associated with Müllerian remnants.

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.

As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys of their age.

During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may develop breast tissue and also have weaker bones, and a lower energy level than other males.

By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no sign of affectedness, a , youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue). Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.

Affected males are often infertile, or may have reduced fertility. Advanced reproductive assistance is sometimes possible.

The term "hypogonadism" in XXY symptoms is often misinterpreted to mean "small testicles" when it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism (i.e., small testicles).

The testicle size of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width and 4 ml in volume.

XXY males are also more likely than other men to have certain health problems that typically affect females, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

Some degree of language learning or reading impairment may be present, and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention. There may also be delays in motor development which can be addressed through occupational therapy and physical therapy. XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports.

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).

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.

The testicle or testis is the male reproductive gland in all animals, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testosterone. Testosterone release is controlled by the anterior pituitary luteinizing hormone; whereas sperm production is controlled both by the anterior pituitary follicle-stimulating hormone and gonadal testosterone.

Many men who were born with undescended testes have reduced fertility, even after orchiopexy in infancy. The reduction with unilateral cryptorchidism is subtle, with a reported infertility rate of about 10%, compared with about 6% reported by the same study for the general population of adult men.

The fertility reduction after orchiopexy for bilateral cryptorchidism is more marked, about 38%, or 6 times that of the general population. The basis for the universal recommendation for early surgery is research showing degeneration of spermatogenic tissue and reduced spermatogonia counts after the second year of life in undescended testes. The degree to which this is prevented or improved by early orchiopexy is still uncertain.

There is a small body of research on the psychology of cryptorchidism, that attempts to determine whether this condition can cause lasting psychological problems. The psychological research on cryptorchism consists of only a few case reports and small studies. This research also has serious methodological problems: major variables are completely uncontrolled, such as the small physical stature of many cryptorchid boys, and the psychological effects of corrective surgery.

Existing research indicates that boys with undescended testicles do not tend to be gender-disordered, effeminate, or pre-homosexual. A disturbed self-image forms only when the family dynamics are destructive to developing male self-esteem. Such pathogenic attitudes were found in parents who focused on the boy’s genital defect as a sign of his presumed effeminacy. However, when the cryptorchism is surgically corrected a healthy masculinity becomes possible. The basic sexual normality of these boys was confirmed in a small retrospective study that tested adolescent boys several years after their condition was surgically repaired. They had developed into fairly well-adjusted teenagers without special sexual or gender problems, and with no distinctive traits of psychopathological relevance.

Testicular enlargement is an unspecific sign of various testicular diseases, and can be defined as a testicular size of more than 5 cm (long axis) x 3 cm (short axis).

Blue balls is a slang term for a temporary fluid congestion in the testicles and prostate region caused by prolonged sexual arousal.

Testicular prostheses are available to mimic the appearance and feel of one or both testicles, when absent as from injury or as treatment in association to gender dysphoria. There have also been some instances of their implantation in dogs.

Symptoms vary from case to case, and may correlate to how much of the chromosome is missing. Symptoms that are frequently observed with the condition include:

- Low birth weight

- Malformations of the head

- Eye abnormalities

- Defects of the hands and feet, polydactyly

- Reproductive abnormalities (males)

- Psychological and motor retardation

Partial monosomy of chromosome 13q is a monosomy that results from the loss of all or part of the long arm of chromosome 13 in human beings. It is a rare genetic disorder which results in severe congenital abnormalities which are frequently fatal at an early age. Up until 2003, more than 125 cases had been documented in medical literature.

Appearance at birth and during the early years is normal but features become more prominent during later childhood prior to puberty. The main issues appear to be lipodystrophy (see below) and slow growth of cartilage and ligaments. The slow growth of cartilage and ligaments results in a small nose, small mandible (jaw), small ears and tightening of ligaments in the limbs. A small larynx (due to

the reduced growth of cartilage) can mean the voice is likely to remain high pitched (even in boys after puberty).

Young–Madders syndrome is detectable from the fetal stage of development largely due to the distinctive consequences of holoprosencephaly, a spectrum of defects or malformations of the brain and face. Facial defects which may manifest in the eyes, nose, and upper lip, featuring cyclopia, anosmia, or in the growth of only a single central incisor, and severe overlapping of the bones of the skull. Cardiac and in some cases pulmonary deformities are present. Another signature deformity is bilateral polydactyly, and many patients also suffer from hypoplasia and genital deformities.

The diagnosis of MDP syndrome is suggested by the clinical features. It can be confirmed by finding a mutation in the POLD1 gene, a service offered by the molecular genetics team at the Royal Devon and Exeter NHS Foundation Trust / Exeter University who originally discovered the genetic cause.

Young–Madders syndrome, alternatively known as Pseudotrisomy 13 syndrome or holoprosencephaly–polydactyly syndrome, is a genetic disorder resulting from defective and duplicated chromosomes which result in holoprosencephaly, polydactyly, facial malformations and mental retardation, with a significant variance in the severity of symptoms being seen across known cases. Many cases often suffer with several other genetic disorders, and some have presented with hypoplasia, cleft lip, cardiac lesions and other heart defects. In one case in 1991 and another in 2000 the condition was found in siblings who were the product of incest. Many cases are diagnosed prenatally and often in siblings. Cases are almost fatal in the prenatal stage with babies being stillborn.

Though it is now thought that earlier cases were misdiagnosed as other genetic disorders with similar pathology—such as Smith–Lemli–Opitz syndrome—the earliest publicised recognition of the condition as a new, hitherto unclassified, genetic disorder was made by two British doctors in Leicester in 1987. Though they identified the condition, later named for them, they did not identify the genetic anomalies responsible but suspected a link with trisomy 13 due to the similar symptoms. With only one or two occurrences documented towards the end of the decade, a group of eight doctors published a five-patient case-study in 1991 which identified the likely chromosomal factors that caused the condition, similar to but distinct from trisomy 13, and gave it the name 'holoprosencephaly–polydactyly syndrome' based on its two most prolific presenting conditions. Later research showed that the condition could manifest in patients with normal karyotypes, without duplication of the chromosomes, and the most recent genetic research implicates problems with the gene code FBXW11 as a likely cause.

Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division. There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).

Calvin Bridges and Thomas Hunt Morgan are credited with discovering nondisjunction in "Drosophila melanogaster" sex chromosomes in the spring of 1910, while working in the Zoological Laboratory of Columbia University.

Of those fetuses that do survive to gestation and subsequent birth, common abnormalities may include:

- Nervous system

- Intellectual disability and motor disorder

- Microcephaly

- Holoprosencephaly (failure of the forebrain to divide properly).

- Structural eye defects, including microphthalmia, Peters' anomaly, cataract, iris or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia

- Meningomyelocele (a spinal defect)

- Musculoskeletal and cutaneous

- Polydactyly (extra digits)

- Cyclopia

- Proboscis

- Congenital trigger digits

- Low-set ears

- Prominent heel

- Deformed feet known as rocker-bottom feet

- Omphalocele (abdominal defect)

- Abnormal palm pattern

- Overlapping of fingers over thumb

- Cutis aplasia (missing portion of the skin/hair)

- Cleft palate

- Urogenital

- Abnormal genitalia

- Kidney defects

- Other

- Heart defects (ventricular septal defect) (Patent Ductus Arteriosus)

- Dextrocardia

- Single umbilical artery

Tricho-hepato-enteric syndrome is one particular form of intractable diarrhea of infancy, presenting typically in the first month of life. These babies were usually born small for their age and continue to experience failure to thrive, usually with a final short stature. Typical facial features include prominent forehead and cheeks, a broad nasal root and widely spaced eyes (hypertelorism). Their hairs are woolly, easily removed and poorly pigmented. Liver disease is mainly present as cirrhosis or fibrosis, and staining might reveal high iron content of the liver cells (consistent with hemochromatosis). Most evaluated patients had some degree of decrease in intelligence.

Karyotyping involves performing an amniocentesis in order to study the cells of an unborn fetus during metophase 1. Light microscopy can be used to visually determine if aneuploidy is an issue.

Megalocornea (MGCN, MGCN1) is an extremely rare nonprogressive condition in which the cornea has an enlarged diameter, reaching and exceeding 13 mm. It is noted in some patients with Marfan syndrome. It is thought to have two subforms, one with autosomal inheritance and the other X-linked (Xq21.3-q22). The X-linked form is more common and males generally constitute 90% of cases.

Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. The extra genetic material disrupts normal development, causing multiple and complex organ defects.

This can occur either because each cell contains a full extra copy of chromosome 13 (a disorder known as trisomy 13 or trisomy D), or because each cell contains an extra partial copy of the chromosome (i.e., Robertsonian translocation) or because of mosaic Patau syndrome. Full trisomy 13 is caused by nondisjunction of chromosomes during meiosis (the mosaic form is caused by nondisjunction during mitosis).

Like all nondisjunction conditions (such as Down syndrome and Edwards syndrome), the risk of this syndrome in the offspring increases with maternal age at pregnancy, with about 31 years being the average. Patau syndrome affects somewhere between 1 in 10,000 and 1 in 21,700 live births.