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.

Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons.

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.

Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects Sertoli and Leydig cell differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS.

It is a rare condition, with only approximately 60 cases reported as of 1989, and 75 cases as of 2005. However, due to the stigma of intersex conditions and the issues of keeping accurate statistics and records among doctors, it is likely there are more cases than reported.

Most cases of polyorchidism are asymptomatic, and are discovered incidentally, in the course of treating another condition. In the majority of cases, the supernumerary testicle is found in the scrotum.

However, polyorchidism can occur in conjunction with cryptorchidism, where the supernumerary testicle is undescended or found elsewhere in the body. These cases are associated with a significant increase in the incidence of testicular cancer: 0.004% for the general population vs 5.7% for a supernumerary testicle not found in the scrotum.

Polyorchidism can also occur in conjunction with infertility, inguinal hernia, testicular torsion, epididymitis, hydrocele testis and varicocele. However, it is not clear whether polyorchidism causes or aggravates these conditions, or whether the existence of these conditions leads sufferers to seek medical attention and thus become diagnosed with a previously undetected supernumerary testicle.

Because polyorchidism is very uncommon, there is no standard treatment for the condition. Prior to advances in ultrasound technology, it was common practice to remove the supernumerary testicle. Several cases have been described where routine follow-up examinations conducted over a period of years showed that the supernumerary testicle was stable.

A meta-analysis in 2009 suggested removing non-scrotal supernumerary testicles because of the increased risk of cancer, and regular follow-up in the remaining cases to ensure that the supernumerary testicle remains stable.

There is increasing evidence that the harmful products of tobacco smoking may damage the testicles and kill sperm, but their effect on male fertility is not clear. 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.

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.

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:

- Hypogonadotropic hypogonadism due to various causes

- Obesity increases the risk of hypogonadotropic hypogonadism. Animal models indicate that obesity causes leptin insensitivity in the hypothalamus, leading to decreased Kiss1 expression, which, in turn, alters the release of gonadotropin-releasing hormone (GnRH).

- Undiagnosed and untreated coeliac disease (CD). Coeliac men may have reversible infertility. Nevertheless, CD can present with several non-gastrointestinal symptoms that can involve nearly any organ system, even in the absence of gastrointestinal symptoms. Thus, the diagnosis may be missed, leading to a risk of long-term complications. In men, CD can reduce semen quality and cause immature secondary sex characteristics, hypogonadism and hyperprolactinaemia, which causes impotence and loss of libido. The giving of gluten free diet and correction of deficient dietary elements can lead to a return of fertility. It is likely that an effective evaluation for infertility would best include assessment for underlying celiac disease, both in men and women.

- Drugs, alcohol

- Strenuous riding (bicycle riding, horseback riding)

- Medications, including those that affect spermatogenesis such as chemotherapy, anabolic steroids, cimetidine, spironolactone; those that decrease FSH levels such as phenytoin; those that decrease sperm motility such as sulfasalazine and nitrofurantoin

- Genetic abnormalities such as a Robertsonian translocation

Surgery (orchiopexy) to retrieve the testes and position them in the scrotum is the primary treatment. Occasionally they are unsalvageable if located high in the retroperitoneum. During this surgery, the uterus is usually removed and attempts made to dissect away Müllerian tissue from the vas deferens and epididymis to improve the chance of fertility. If the person has male gender identity himself and the testes cannot be retrieved, testosterone replacement will be usually necessary at puberty should the affected individual choose to pursue medical attention. Lately, laparoscopic hysterectomy is offered to patients as a solution to both improve the chances of fertility and to prevent the occurrences of neoplastic tissue formation.

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.

PMDS type I results from mutations of the gene ("AMH") for AMH on chromosome 19p3.3.

PMDS type II results from mutations of the gene ("AMH-RII") for the AMH receptor on 12q13.

Both types of disorders are inherited as autosomal recessive conditions with expression usually limited to XY offspring.

Hypospadias is among the most common birth defects in the world and is said to be the second-most common birth defect in the male reproductive system, occurring once in every 250 males.

Due to variations in the reporting requirements of different national databases, data from such registries cannot be used to accurately determine either incidence of hypospadias or geographical variations in its occurrences.

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.

This can be due to:

- One testicle not descending into the scrotum during normal embryonic or fetal development (3–4% of 'normal' live births), also known as undescended testis or cryptorchidism. In this case the testis is within the abdominal cavity, somewhere along the normal route of descent – most commonly, within the inguinal canal. Such a testis has an increased risk of malignancy.

- One testicle may disappear during development (the so-called vanishing testis) due to some intrauterine insult. This is thought to be most likely vascular, such as testicular torsion.

- One testicle may have been surgically removed through orchiectomy.

- One testicle may be injured.

Although extremely rare, monorchism has been observed to be characteristic of some animal species, notably in beetles.

Congenital anomalies like cryptorchidism, renal agenesis/dysplasia, musculoskeletal and cardiopulmonary anomalies are also common (>50% cases), hence evaluation of the patient for internal anomalies is mandatory.

Although aphallia can occur in any body type, it is considered a substantially more troublesome problem with those who have testes present, and has in the past sometimes been considered justification for assigning and rearing a genetically male infant as a girl. After the theory in the 1950s that gender as a social construct was purely nurture and so an individual child could be raised early on and into one gender or the other regardless of their genetics or brain chemistry. Intersex people generally advocate harshly against coercive genital reassignment however, and encourage infants to be raised choosing their own gender identity. The nurture theory has been largely abandoned and cases of trying to rear children this way have not proven to be successful transitions.

In newborn period or infancy, feminizing operations are recommended for treatment of penile agenesis, but after 2 years, as sexual identification of the patients has appeared, it is advised to perform masculinizing operations in order not to disturb the child psychologically.

Recent advances in surgical phalloplasty techniques have provided additional options for those still interested in pursuing surgery.

The human breast cancer susceptibility gene 2 (BRCA2) is employed in homologous recombinational repair of DNA damages during meiosis. A common single-nucleotide polymorphism of BRCA2 is associated with severe oligospermia.

Men with mild oligospermia (semen concentration of 15 million to 20 million sperm/ml) were studied for an association of sperm DNA damage with life style factors. A significant association was found between sperm DNA damage and factors such as age, obesity and occupational stress.

In about 30% of infertile men no causative factor is found for their decrease in sperm concentration or quality by common clinical, instrumental, or laboratory means, and the condition is termed "idiopathic" (unexplained). A number of factors may be involved in the genesis of this condition, including age, infectious agents ( such as "Chlamydia trachomatis"), Y chromosome microdeletions, mitochondrial changes, environmental pollutants, and "subtle" hormonal changes.

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. It found no significant relation between oligospermia and being underweight.

Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular disorder.

At puberty, most affected individuals require treatment with the male sex hormone testosterone to induce development of male secondary sex characteristics such as facial hair and deepening of the voice (masculinization). Hormone treatment can also help prevent breast enlargement (gynecomastia). Adults with this disorder are usually shorter than average for males and are unable to have children (infertile).

Gonadectomy at time of diagnosis is the current recommendation for PAIS if presenting with cryptorchidism, due to the high (50%) risk of germ cell malignancy. The risk of malignancy when testes are located intrascrotally is unknown; the current recommendation is to biopsy the testes at puberty, allowing investigation of at least 30 seminiferous tubules, with diagnosis preferably based on OCT3/4 immunohistochemistry, followed by regular examinations. Hormone replacement therapy is required after gonadectomy, and should be modulated over time to replicate the hormone levels naturally present in the body during the various stages of puberty. Artificially induced puberty results in the same, normal development of secondary sexual characteristics, growth spurt, and bone mineral accumulation. Women with PAIS may have a tendency towards bone mineralization deficiency, although this increase is thought to be less than is typically seen in CAIS, and is similarly managed.

In posttesticular azoospermia sperm are produced but not ejaculated, a condition that affects 7–51% of azoospermic men. The main cause is a physical obstruction (obstructive azoospermia) of the posttesticular genital tracts. The most common reason is a vasectomy done to induce contraceptive sterility. Other obstructions can be congenital (example agenesis of the vas deferens as seen in certain cases of cystic fibrosis) or acquired, such as ejaculatory duct obstruction for instance by infection.

Ejaculatory disorders include retrograde ejaculation and anejaculation; in these conditions sperm are produced but not expelled.

The decision of whether to raise an individual with PAIS as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype that may be difficult to classify as primarily male or female, and some will be incapable of virilization at puberty. Parents of an affected newborn should seek immediate help at a center with an experienced multidisciplinary team, and should avoid gender assignment beforehand. Gender assignment should thereafter be expeditiously decided; current guidelines advise against waiting for the child to decide for his / herself. Key considerations involved in assigning gender include the appearance of the genitalia, the extent to which the child can virilize at puberty, surgical options and the postoperative sexual function of the genitalia, genitoplasty complexity, potential for fertility, and the projected gender identity of the child. The majority of individuals with PAIS are raised male.

Virilization capacity can be assessed by measuring the response to a trial of exogenous androgens; some studies have measured the growth of the phallus in response to exogenous testosterone or dihydrotestosterone, while others have measured the change in sex hormone binding globulin (SHBG) in response to the artificial androgen stanozolol to assess androgen sensitivity. Some experts have cautioned that it remains to be proved that a good response to exogenous androgens in neonates is a good predictor of androgen response at puberty. If a mutation in the AR gene is found, it is important to determine whether the mutation is inherited or de novo (i.e. a somatic mutation); a certain amount of the wild-type androgen receptor will be present in cases of somatic mutation, which can induce virilization at puberty. A genital skin fibroblast study and a human chorionic gonadotropin (hCG) stimulation test may also provide information helpful in the assessment of virilization capacity.

Psychosexual development is influenced by many factors, including the timing, amount, and type of androgen exposure, receptor functionality, and environment, and is thus difficult to predict. Gender identity begins to develop before 3 years of age, although the earliest age at which it can be reliably assessed has yet to be determined. Approximately 25% of individuals with PAIS are dissatisfied with their assigned gender, regardless of being raised as male or female. One study reports that 46,XY individuals born with micropenis and no hypospadias are better off being raised male, despite the success of some being raised female. Studies involving the more ambiguous phenotypic forms of PAIS are less decisive. Homosexuality with respect to assigned gender and atypical gender role behavior are known to occur more frequently in individual with PAIS, and may occur with or without gender dysphoria; neither should be interpreted as an indication of incorrect gender assignment. If an affected child does express feelings of gender dysphoria, the opportunity to explore such feelings with a psychologist experienced in treating intersex conditions should be accommodated. If feelings of gender dysphoria persist, gender reassignment should be initiated, possibly with the aid of a specialist in the field.