Examples of symptoms of hypogonadism with underdevelopment of the Gonads (testicles and ovaries) include delayed, reduced, or absent puberty, low libido, and infertility.

Examples of symptoms of hypogonadism include delayed, reduced, or absent puberty, low libido, and infertility.

Women with hypogonadism do not begin menstruating and it may affect their height and breast development. Onset in women after puberty causes cessation of menstruation, lowered libido, loss of body hair and hot flashes. In boys it causes impaired muscle and beard development and reduced height. In men it can cause reduced body hair and beard, enlarged breasts, loss of muscle, and sexual difficulties. A brain tumor (central hypogonadism) may involve headaches, impaired vision, milky discharge from the breast and symptoms caused by other hormone problems.

The symptoms of hypogonadotrophic hypogonadism, a subtype of hypogonadism, include late, incomplete or lack of development at puberty, and sometimes short stature or the inability to smell; in females, a lack of breasts and menstrual periods, and in males a lack of sexual development, e.g., facial hair, penis and testes enlargement, deepening voice.

The exact genetic nature of each particular case of KS / HH will determine which, if any, of the non-reproductive features will occur. The severity of the symptoms will also vary from case to case. Even family members will not show the same range or severity of symptoms.

KS / HH is most often present from birth but adult onset versions are found in both males and females. The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life giving normal puberty and normal reproductive function. The HPG axis then either fails totally or is reduced to a very low level of GnRH release, in adult life with no obvious cause such as a pituitary tumour. This will lead to a fall in testosterone or oestrogen levels and infertility.

Functional hypothalamic amenorrhoea is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition. It is reversible with the removal of the stressor.

Some cases of KS / HH appear to reverse during adult life where the HPG axis resumes its normal function and GnRH, LH, and FSH levels return to normal levels. This occurs in an estimated 10 to 20% of cases, primarily normosmic CHH cases rather than KS cases and only found in patients who have undergone some form of testosterone replacement therapy.

It is only normally discovered when testicular volume increases while on testosterone treatment alone and testosterone levels return to normal when treatment is stopped. This type of KS / HH rarely occurs in cases where males have had a history of un-descended testes.

Affected individuals with KS and other forms of HH are almost invariably born with normal sexual differentiation; i.e., they are physically male or female. This is due to the human chorionic gonadotrophin (hCG) produced by placenta at approximately 12 to 20 weeks gestation (pregnancy) which is normally unaffected by having KS or CHH.

People with KS / HH lack the surge of GnRH, LH, and FSH that normally occurs between birth and six months of age. This surge is particularly important in infant boys as it helps with testicular descent into the scrotum. The surge of GnRH/LH/FSH in non KS/HH children gives detectable levels of testosterone in boys and oestrogen & progesterone in girls. The lack of this surge can sometimes be used as a diagnostic tool if KS / HH is suspected in a newborn boy, but is not normally distinct enough for diagnosis in girls.

The symptoms of isolated 17,20-lyase deficiency, in males, include pseudohermaphroditism (i.e., feminized, ambiguous, or mildly underdeveloped (e.g., micropenis, perineal hypospadias, and/or cryptorchidism (undescended testes)) external genitalia), female gender identity, and, in non-complete cases of deficiency where partial virilization occurs, gynecomastia up to Tanner stage V (due to low androgen levels, which results in a lack of suppression of estrogen); in females, amenorrhoea or, in cases of only partial deficiency, merely irregular menses, and enlarged cystic ovaries (due to excessive stimulation by high levels of gonadotropins); and in both sexes, hypergonadotropic hypogonadism (hypogonadism despite high levels of gonadotropins), delayed, impaired, or fully absent adrenarche and puberty with an associated reduction in or complete lack of development of secondary sexual characteristics (sexual infantilism), impaired fertility or complete sterility, tall stature (due to delayed epiphyseal closure), eunuchoid skeletal proportions, delayed or absent bone maturation, and osteoporosis.

It is normally difficult to distinguish a case of KS / HH from a straightforward constitutional delay of puberty. However, if puberty has not started by either age 14 (girls) or 15 (boys) and one or more of the non-reproductie features mentioned belowe is present then a referral to reproductive endocrinologist might be advisable.

The features of Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) can be split into two different categories; "reproductive" and "non reproductive".

Congenital hypogonadotropic hypogonadism presents as hypogonadism, e.g., reduced or absent puberty, low libido, infertility, etc. due to an impaired release of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and a resultant lack of sex steroid and peptides production by the gonads.

In Kallmann syndrome, a variable non-reproductive phenotype occurs with anosmia (loss of the sense of smell) including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis.

Hypogonadotropic hypogonadism (HH), also known as secondary or central hypogonadism, as well as gonadotropin-releasing hormone deficiency or gonadotropin deficiency (GD), is a condition which is 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.

Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism, is a condition which is characterized by hypogonadism due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production and elevated gonadotropin levels (as an attempt of compensation by the body). HH may present as either "congenital" or "acquired", but the majority of cases are of the former nature.

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.

The symptoms of Leydig cell hypoplasia include pseudohermaphroditism (i.e., feminized, ambiguous, or relatively mildly underdeveloped (e.g., micropenis, severe hypospadias, and/or cryptorchidism (undescended testes)) external genitalia), a female gender identity or gender variance, hypergonadotropic hypogonadism (hypogonadism despite high levels of gonadotropins), delayed, impaired, or fully absent puberty with an associated reduction in or complete lack of development of secondary sexual characteristics (sexual infantilism), impaired fertility or complete sterility, tall stature (due to delayed epiphyseal closure), eunuchoid skeletal proportions, delayed or absent bone maturation, and osteoporosis.

Symptoms of the condition in males consist of loss of libido, impotence, infertility, shrinkage of the testicles, penis, and prostate, diminished masculinization (e.g., decreased facial and body hair growth), low muscle mass, anxiety, depression, fatigue, vasomotor symptoms (hot flashes), insomnia, headaches, and osteoporosis. In addition, symptoms of hyperestrogenism, such as gynecomastia and feminization, may be concurrently present in males.

In females, hypoandrogenism consist of loss of libido, decreased body hair growth, depression, fatigue, vaginal vasocongestion (which can result in cramps), vasomotor symptoms (e.g., hot flashes and palpitations), insomnia, headaches, osteoporosis and reduced muscle mass. Symptoms of hypoestrogenism may be present in both sexes in cases of severe androgen deficiency (as estrogens are synthesized from androgens).

FSH insensitivity presents itself in females as two clusters of symptoms: 1) hypergonadotropic hypogonadism or hypoestrogenism, resulting in a delayed, reduced, or fully absent puberty and associated sexual infantilism (if left untreated), reduced uterine volume, and osteoporosis; and 2) ovarian dysgenesis or failure, resulting in primary or secondary amenorrhea, infertility, and normal sized to slightly enlarged ovaries. Males on the other hand are significantly less affected, presenting merely with partial or complete infertility, reduced testicular volume, and oligozoospermia (reduced spermatogenesis).

Isolated 17,20-lyase deficiency (ILD), also called isolated 17,20-desmolase deficiency, is a rare endocrine and autosomal recessive genetic disorder which is characterized by a complete or partial loss of 17,20-lyase activity and, in turn, impaired production of the androgen and estrogen sex steroids. The condition manifests itself as pseudohermaphroditism (partially or fully underdeveloped genitalia) in males, in whom it is considered to be a form of intersex, and, in both sexes, as a reduced or absent puberty/lack of development of secondary sexual characteristics, resulting in a somewhat childlike appearance in adulthood (if left untreated).

Unlike the case of combined 17α-hydroxylase/17,20-lyase deficiency, isolated 17,20-lyase deficiency does not affect glucocorticoid production (or mineralocorticoid levels), and for that reason, does not result in adrenal hyperplasia or hypertension.

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.

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

Observed physiological abnormalities of the condition include a dramatic overexpression of aromatase and, accordingly, excessive levels of estrogens including estrone and estradiol and a very high rate of peripheral conversion of androgens to estrogens. In one study, cellular aromatase mRNA expression was found to be at least 10 times higher in a female patient compared to the control, and the estradiol/testosterone ratio after an injection of testosterone in a male patient was found to be 100 times greater than the control. Additionally, in another study, androstenedione, testosterone, and dihydrotestosterone (DHT) were found to be either low or normal in males, and follicle-stimulating hormone (FSH) levels were very low (likely due to suppression by estrogen, which has antigonadotropic effects as a form of negative feedback inhibition on sex steroid production in sufficiently high amounts), whereas luteinizing hormone (LH) levels were normal.

According to a recent review, estrone levels have been elevated in 17 of 18 patients (94%), while estradiol levels have been elevated only in 13 of 27 patients (48%). As such, estrone is the main estrogen elevated in the condition. In more than half of patients, circulating androstenedione and testosterone levels are low to subnormal. The ratio of circulating estradiol to testosterone is >10 in 75% of cases. FSH levels are said to be consistently low in the condition, while LH levels are in the low to normal range.

It is notable that gynecomastia has been observed in patients in whom estradiol levels are within the normal range. This has been suggested to be due to "in situ" conversion of adrenal androgens into estrone and then estradiol (via local 17β-HSD) in breast tissue (where aromatase activity may be particularly high).

The symptoms of AES, in males, include heterosexual precocity (precocious puberty with phenotypically-inappropriate secondary sexual characteristics; i.e., a fully or mostly feminized appearance), severe prepubertal or peripubertal gynecomastia (development of breasts in males before or around puberty), high-pitched voice, sparse facial hair, hypogonadism (dysfunctional gonads), oligozoospermia (low sperm count), small testes, micropenis (an ususually small penis), advanced bone maturation, an earlier peak height velocity (an accelerated rate of growth in regards to height), and short final stature due to early epiphyseal closure. The incidence of gynecomastia appears to be 100%, with 20 of 30 male cases opting for mastectomy according to a review.

In females, symptoms of AES include isosexual precocity (precocious puberty with phenotypically-appropriate secondary sexual characteristics), macromastia (excessively large breasts), an enlarged uterus, menstrual irregularities, and, similarly to males, accelerated bone maturation and short final height. Of seven females described in one report, three had macromastia (rate of ~43%). A 10-year-old girl with gigantomastia has subsequently also been described.

Fertility, though usually affected to one degree or another—especially in males—is not always impaired significantly enough to prevent sexual reproduction, as evidenced by vertical transmission of the condition by both sexes.

Leydig cell hypoplasia (or aplasia) (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism (partially or fully underdeveloped genitalia), 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), and infertility.

Leydig cell hypoplasia does not occur in biological females as they do not have either Leydig cells or testicles. However, the cause of the condition in males, luteinizing hormone insensitivity, does affect females, and because LH plays a role in the female reproductive system, it can result in primary amenorrhea or oligomenorrhea (absent or reduced menstruation), infertility due to anovulation, and ovarian cysts.

A related condition is follicle-stimulating hormone (FSH) insensitivity, which presents with similar symptoms to those of Leydig cell hypoplasia but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in females and merely problems with fertility in males). Despite their similar causes, FSH insensitivity is considerably less common in comparison to LH insensitivity.

Hypoandrogenism is caused primarily by either dysfunction, failure, or absence of the gonads ("hypergonadotropic") or impairment of the hypothalamus or pituitary gland ("hypogonadotropic"), which in turn can be caused by a multitude of different stimuli, including genetic conditions (e.g., GnRH/gonadotropin insensitivity and enzymatic defects of steroidogenesis), tumors, trauma, surgery, autoimmunity, radiation, infections, toxins, drugs, and many others. Alternatively, it may be the result of conditions such as androgen insensitivity syndrome or hyperestrogenism. More simply, old age may also be a factor in the development of hypoandrogenism, as androgen levels decline with age.

Aromatase excess syndrome (AES or AEXS), also sometimes referred to as familial hyperestrogenism or familial gynecomastia, is a rare genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization (with the exception of the genitalia; i.e., no pseudohermaphroditism) and in females as hyperfeminization.

To date, 30 males and 8 females with AES among 15 and 7 families, respectively, have been described in the medical literature.

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.

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.

Gonadotropin-releasing hormone (GnRH) insensitivity is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Swyer syndrome represents one phenotypic result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis. There are many forms of gonadal dysgenesis.

Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome.