Reversal of symptoms have been reported in between 15% to 22% of cases. The causes of this reversal are still under investigation but have been reported in both males and females.

Reversal appears to be associated with 14 of the known gene defects linked to KS/CHH. The study suggests no obvious gene defect showing a tendency to allow reversal. There is a suggestion that the TAC3 and TACR3 mutations might allow for a slightly higher chance of reversal, but the numbers involved are too low to confirm this. The ANOS1 mutations appear to be least likely to allow reversal with to date only one recorded instance in medical literature. Even male patients who previous had micro-phallus or cryptorchidism have been shown to undergo reversal of symptoms.

The reversal might not be permanent and remission can occur at any stage; the paper suggests that this could be linked to stress levels. The paper highlighted a reversal case that went into remission but subsequently achieved reversal again, strongly suggesting an environmental link.

Reversal cases have been seen in cases of both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). A paper published in 2016 agreed with the theory that there is a strong environmental or epigenetic link to the reversal cases. The precise mechanism of reversal is unclear and is an area of active research.

Reversal would be apparent if testicular development was seen in men while on testosterone therapy alone or in women who menstruate or achieved pregnancy while on no treatment. To date there have been no recorded cases of the reversal of anosmia found in Kallmann syndrome cases.

To date at least twenty five different genes have been implicated in causing Kallmann syndrome or other forms of HH through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance and no one gene defect has been shown to be common to all cases which makes genetic testing and inheritance prediction difficult.

The number of genes known to cause cases of KS / CHH is still increasing. In addition it is thought that some cases of KS / CHH are caused by two separate gene defects occurring at the same time. Around 50% of cases have an unknown genetic origin.

Some of the genes known to be involved in cases of KS / CHH are listed in the Online Mendelian Inheritance in Man ((OMIM)) table at the end of this article.

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.

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

Several treatments have been found to be effective in managing AES, including aromatase inhibitors and gonadotropin-releasing hormone analogues in both sexes, androgen replacement therapy with non-aromatizable androgens such as DHT in males, and progestogens (which, by virtue of their antigonadotropic properties at high doses, suppress estrogen levels) in females. In addition, male patients often seek bilateral mastectomy, whereas females may opt for breast reduction if warranted.

Medical treatment of AES is not absolutely necessary, but it is recommended as the condition, if left untreated, may lead to excessively large breasts (which may necessitate surgical reduction), problems with fertility, and an increased risk of endometriosis and estrogen-dependent cancers such as breast and endometrial cancers later in life. At least one case of male breast cancer has been reported.

The root cause of AES is not entirely clear, but it has been elucidated that inheritable, autosomal dominant genetic mutations affecting "CYP19A1", the gene which encodes aromatase, are involved in its etiology. Different mutations are associated with differential severity of symptoms, such as mild to severe gynecomastia.

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.

Based on its cause, the type of hypogonadotropic hypogonadism (HH) may be classified as either "primary" or "secondary".

"Primary" HH, also called isolated hypogonadotropic hypogonadism, is responsible for only a small subset of cases of HH, and is characterized by an otherwise normal function and anatomy of the hypothalamus and anterior pituitary. It is caused by congenital disorders such as Kallmann syndrome, CHARGE syndrome, and gonadotropin-releasing hormone insensitivity.

"Secondary" HH, also known as acquired or syndromic HH, is far more common than primary HH, and responsible for most cases of the condition. It has a multitude of different causes, including brain or pituitary tumors, pituitary apoplexy, head trauma, ingestion of certain drugs, and certain systemic diseases and syndromes.

Primary and secondary HH can also be attributed to a genetic trait inherited from the biologic parents. For example, the male mutations of the GnRH coding gene could result in HH. Hormone replacement can be used to initiate puberty and continue if the gene mutation occurs in the gene coding for the hormone. Chromosomal mutations tend to affect the androgen production rather than the HPG axis.

IHH is divided into two syndromes: IHH with olfactory alterations or anosmia, Kallmann syndrome and IHH with normal smell (normosmic IHH).

Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in "KAL1", "FGFR1/FGF8", "FGF17", "IL17RD", "PROKR2", "NELF", "CHD7"(which positively regulates GnRH secretion), HS6ST1, "FLRT3", "SPRY4", DUSP6, "SEMA3A", and "WDR11 (gene)", genes which are related to defects in neuronal migration.

Gene defects associated with IHH and normal smell include "PROKR2, FGFR1, FGF8, CHD7, DUSP6," and "WDR11", as in KS, but in addition

also mutations in "KISS1R", "TACR3", GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB.

GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases.

A minority of less than 5-10% is due to inactivating mutations in genes which positively regulate GnRH secretion such as ,"CHD7", "KISS1R", and "TACR3".

The causes of about 25% of all IHH cases are still unknown.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD) constitutes a small subset of cases of hypogonadotropic hypogonadism (HH).

IHH is due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH), where the function and anatomy of the anterior pituitary is otherwise normal, and secondary causes of HH are not present.

Treatment of HH is usually with hormone replacement therapy, consisting of androgen and estrogen administration in males and females, respectively.

Hypogonadotropic hypogonadism (HH), also known as secondary or central hypogonadism, as well as gonadotropin-releasing hormone deficiency or gonadotropin deficiency (GD), is a medical condition characterized by hypogonadism due to an impaired secretion of gonadotropins, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH), by the pituitary gland in the brain, and in turn decreased gonadotropin levels and a resultant lack of sex steroid production.

Hormone replacement therapy with estrogen may be used to treat symptoms of hypoestrogenism in females with the condition. There are currently no known treatments for the infertility caused by the condition in either sex.

Males and females may be treated with hormone replacement therapy (i.e., with androgens and estrogens, respectively), which will result in normal sexual development and resolve most symptoms. In the case of 46,XY (genetically male) individuals who are phenotypically female and/or identify as the female gender, they should be treated with estrogens instead. Removal of the undescended testes should be performed in 46,XY females to prevent their malignant degeneration, whereas in 46,XY males surgical correction of the genitals is generally required, and, if necessary, an orchidopexy (relocation of the undescended testes to the scrotum) may be performed as well. Namely in genetic females presenting with ovarian cysts, GnRH analogues may be used to control high FSH and LH levels if they are unresponsive to estrogens.

Isolated 17,20-lyase deficiency is caused by genetic mutations in the gene "CYP17A1", which encodes for 17,20-lyase, while not affecting 17α-hydroxylase, which is encoded by the same gene.

Observed physiological abnormalities of the condition include markedly elevated serum levels of progestogens such as progesterone and 17α-hydroxyprogesterone (due to upregulation of precursor availability for androgen and estrogen synthesis), very low or fully absent peripheral concentrations of androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone and estrogens such as estradiol (due to the lack of 17,20-lyase activity, which is essential for their production), and high serum concentrations of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (due to a lack of negative feedback on account of the lack of sex hormones).

There are a multitude of different etiologies of HH. Congenital causes include the following:

- Chromosomal abnormalities (resulting in gonadal dysgenesis) - Turner's syndrome, Klinefelter's syndrome, Swyer's syndrome, XX gonadal dysgenesis, and mosaicism.

- Defects in the enzymes involved in the gonadal biosynthesis of the sex hormones - 17α-hydroxylase deficiency, 17,20-lyase deficiency, 17β-hydroxysteroid dehydrogenase III deficiency, and lipoid congenital adrenal hyperplasia.

- Gonadotropin resistance (e.g., due to inactivating mutations in the gonadotropin receptors) - Leydig cell hypoplasia (or insensitivity to LH) in males, FSH insensitivity in females, and LH and FSH resistance due to mutations in the "GNAS" gene (termed pseudohypoparathyroidism type 1A).

Acquired causes (due to damage to or dysfunction of the gonads) include ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted diseases), toxins (e.g., endocrine disruptors), and drugs (e.g., antiandrogens, opioids, alcohol).

XX gonadal dysgenesis is related to the Swyer syndrome inasmuch as both conditions have the same phenotype and clinical issues; however in Swyer syndrome the karyotype is 46,XY, and thus gonadectomy is recommended.

In Turner syndrome there is a demonstrable abnormality in or absence of one of the sex chromosomes that is the cause of the development of gonadal dysgenesis. In contrast XX gonadal dysgenesis has a normal female chromosome situation.

Another type of XX gonadal dysgenesis is known as 46,XX gonadal dysgenesis epibulbar dermoid, which follows the similar symptoms as the regular syndrome, though it also shows signs of epibulbar dermoid (eye disorder). It has been suggested to be a new type of syndrome.

Approximate mean ages for the onset of various pubertal changes are as follows. Ages in parentheses are the approximate 3rd and 97th percentiles for attainment. For example, less than 3% of girls have not yet achieved thelarche by 13 years of age. Developmental changes during puberty in girls occur over a period of 3 – 5 years, usually between 10 and 15 years of age. They include the occurrence of secondary characteristics beginning with breast development, the adolescent growth spurt, the onset of menarche – which does not correspond to the end of puberty – and the acquisition of fertility, as well as profound psychological modifications.

The normal variation in the age at which adolescent changes occur is so wide that puberty cannot be considered to be pathologically delayed until the menarche has failed to occur by the age of 18 or testicular development by the age of 20.

The sources of the data, and a fuller description of normal timing and sequence of pubertal events, as well as the hormonal changes that drive them, are provided in the principal article on puberty. It is worthwhile to consider the world geographical and ethnographic/demographic limits and deficits of this study.

Deficiency of sex hormones can result in defective primary or secondary sexual development, or withdrawal effects (e.g., premature menopause) in adults. Defective egg or sperm development results in infertility. The term hypogonadism usually means permanent rather than transient or reversible defects, and usually implies deficiency of reproductive hormones, with or without fertility defects. The term is less commonly used for infertility without hormone deficiency. There are many possible types of hypogonadism and several ways to categorize them. Hypogonadism is also categorized by endocrinologists by the level of the reproductive system that is defective. Physicians measure gonadotropins (LH and FSH) to distinguish primary from secondary hypogonadism. In primary hypogonadism the LH and/or FSH are usually elevated, meaning the problem is in the testicles, whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain.

The fertile eunuch syndrome is a cause of hypogonadotropic hypogonadism caused by a luteinizing hormone deficiency. It is characterized by hypogonadism with spermatogenesis. Pasqualini and Bur published the first case of eunuchoidism with preserved spermatogenesis in 1950 in la Revista de la Asociación Médica Argentina.

The hypoandrogenism with spermatogenesis syndrome included: (a) eunuchoidism, (b) testis with normal spermatogenesis and full volume, with mature spermatozoids in a high proportion of seminiferous tubes and undifferentiated and immature Leydig cells (c) full functional compensation through the administration of chorionic gonadotropin hormone, while hCG is administered (d) total urinary gonadotrophins within normal limits (e) this definition implies the normal activity of the pituitary and the absence of congenital malformations in general. In describing five other similar cases in 1953, Mc Cullagh & al coined the term fertile eunuch introducing it in the English literature. Unfortunately, this term is incorrect and should not be employed. Indeed, these patients are not really eunuchs. Moreover, as it will be explained later, they are not usually fertile if not treated.

A first step in the understanding of the physiopathology of Pasqualini syndrome was the absence of Lutheinizing Hormone (LH) in plasma and urine of patients. The second breakthrough was the functional and genetic studies that validated the hypothesis of a functional deficit of LH in these men. Inactivating LH mutations will then also be described in some women. Different groups demonstrated in these cases a LH with varying degrees of immunological activity but biologically inactive in most of the patients, due to one or more inactivating mutations in the LHB gene. Finally, the full comprehension of Pasqualini syndrome allowed to reverse the hypoandrogenic phenotype and to restore fertility in these patients through the use of chorionic gonadotropin and the modern in-vitro fertility techniques

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism (decreased or lack of production of sex steroids by the gonads despite high circulating levels of gonadotropins), reduced or absent puberty (lack of development of secondary sexual characteristics, resulting in sexual infantilism if left untreated), amenorrhea (lack of menstruation), and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms (e.g., decreased sperm production).

A related condition is luteinizing hormone (LH) insensitivity (termed Leydig cell hypoplasia when it occurs in males), which presents with similar symptoms to those of FSH insensitivity but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in males and merely problems with fertility in females); however, males also present with feminized or ambiguous genitalia (also known as pseudohermaphroditism), whereas ambiguous genitalia does not occur in females with FSH insensitivity. Despite their similar causes, LH insensitivity is considerably more common in comparison to FSH insensitivity.

If a child is healthy but simply late, reassurance and prediction based on the bone age can be provided. No other intervention is usually necessary. In more extreme cases of delay, or cases where the delay is more extremely distressing to the child, a low dose of testosterone or estrogen for a few months may bring the first reassuring changes of normal puberty.

If the delay is due to systemic disease or undernutrition, the therapeutic intervention is likely to focus mainly on those conditions. In patients with coeliac disease, an early diagnosis and the establishment of a gluten-free diet prevents long-term complications and allows restore normal maturation.

If it becomes clear that there is a permanent defect of the reproductive system, treatment usually involves replacement of the appropriate hormones (testosterone/dihydrotestosterone for boys, estradiol and progesterone for girls).

Pubertal delay due to gonadotropin deficiency is treated with testosterone replacement or with HCG.

Growth hormone is another option that has been described.

Subnormal vitamin A intake is one of the aetiological factors in delayed pubertal maturation. Supplementation of both vitamin A and iron to normal constitutionally delayed children with subnormal vitamin A intake is as efficacious as hormonal therapy in the induction of growth and puberty.

Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.

- Examples of hypogonadism that affect hormone production more than fertility are hypopituitarism and Kallmann syndrome; in both cases, fertility is reduced until hormones are replaced but can be achieved solely with hormone replacement.

- Examples of hypogonadism that affect fertility more than hormone production are Klinefelter syndrome and Kartagener syndrome.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

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.