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.

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.

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

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

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.

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.

Hirsutism can be caused by either an increased level of androgens, the male hormones, or an oversensitivity of hair follicles to androgens. Male hormones such as testosterone stimulate hair growth, increase size and intensify the growth and pigmentation of hair. Other symptoms associated with a high level of male hormones include acne, deepening of the voice, and increased muscle mass. The condition is called hyperandrogenism.

Growing evidence implicates high circulating levels of insulin in women for the development of hirsutism. This theory is speculated to be consistent with the observation that obese (and thus presumably insulin resistant hyperinsulinemic) women are at high risk of becoming hirsute. Further, treatments that lower insulin levels will lead to a reduction in hirsutism.

It is speculated that insulin, at high enough concentration, stimulates the ovarian theca cells to produce androgens. There may also be an effect of high levels of insulin to activate insulin-like growth factor 1 (IGF-1) receptor in those same cells. Again, the result is increased androgen production.

Signs that are suggestive of an androgen-secreting tumor in a patient with hirsutism is rapid onset, virilization and palpable abdominal mass.

The following are conditions and situations that have been associated with hyperandrogenism and hence hirsutism in women:

- Hyperinsulinemia (insulin excess) or hypoinsulinemia (insulin deficiency or resistance as in diabetes).

- Ovarian cysts such as in polycystic ovary syndrome (PCOS), the most common cause in women.

- Ovarian tumors such as granulosa tumors, thecomas, Sertoli–Leydig cell tumors (androblastomas), and gynandroblastomas, as well as ovarian cancer.

- Hyperthecosis.

- Pregnancy.

- Adrenal gland tumors, adrenocortical adenomas, and adrenocortical carcinoma, as well as adrenal hyperplasia due to pituitary adenomas (as in Cushing's syndrome).

- hCG-secreting tumors

- Inborn errors of steroid metabolism such as in congenital adrenal hyperplasia, most commonly caused by 21-hydroxylase deficiency.

- Acromegaly and gigantism (growth hormone and IGF-1 excess), usually due to pituitary tumors.

- Use of certain medications such as androgens/anabolic steroids, phenytoin, and minoxidil.

Causes of hirsutism not related to hyperandrogenism include:

- Porphyria cutanea tarda.

- Minoxidil

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).

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.

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.

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.

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.

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.

Hirsutism affects members of any gender, since rising androgen levels can cause excessive body hair, particularly in locations where women normally do not develop terminal hair during puberty (chest, abdomen, back, and face). The medical term for excessive hair growth that affects any gender is hypertrichosis.

FSH insensitivity is caused by inactivating mutations of the follicle-stimulating hormone receptor (FSHR) and thus an insensitivity of the receptor to FSH. This results in an inability of the granulosa cells in ovarian follicles to respond to FSH in females, in turn resulting in diminished estrogen production by the ovaries and loss of menstrual cycles, and an inability of Sertoli cells in the seminiferous tubules of the testicles to respond to FSH in males, which in turn results in impaired spermatogenesis.

The epidemiology of Kallmann's is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army found a prevalence of 1 in 86,000 men and a 2011 report from Finland found a prevalence of 1:30,000 for males and 1:125,000 for females.

There is 4 to 5:1 ratio of men to women among all people with Kallmann syndrome; in familial Kallmann the ratio is lower, at 2.5 to 1.

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.

Hyperestrogenism can be caused by ovarian tumors, genetic conditions such as aromatase excess syndrome (also known as familial hyperestrogenism), or overconsumption of exogenous sources of estrogen, including medications used in hormone replacement therapy and hormonal contraception. Liver cirrhosis is another cause, though through lowered metabolism of estrogen, not oversecretion or overconsumption like the aforementioned.

Androgen deficiency is not usually checked for diagnosis in healthy women.

Approximately 10–25 percent of cases are estimated to result from the use of medications. This is known as non-physiologic gynecomastia. Medications known to cause gynecomastia include ketoconazole, cimetidine, gonadotropin-releasing hormone analogues, human growth hormone, human chorionic gonadotropin, 5α-Reductase inhibitors such as finasteride and dutasteride, estrogens such as those used in transgender women and men with prostate cancer, and antiandrogens such as bicalutamide, flutamide, and spironolactone. Medications that are probably associated with gynecomastia include calcium channel blockers such as verapamil, amlodipine, and nifedipine; risperidone, olanzapine, anabolic steroids, alcohol, opioids, efavirenz, alkylating agents, and omeprazole. Certain components of personal care products such as lavender or tea tree oil and certain supplements such as dong quai and "Tribulus terrestris" have been associated with gynecomastia.

Treatment may consist of surgery in the case of tumors, lower doses of estrogen in the case of exogenously-mediated estrogen excess, and estrogen-suppressing medications like gonadotropin-releasing hormone analogues and progestogens. In addition, androgens may be supplemented in the case of males.

Gynecomastia is the most common benign disorder of the male breast tissue. New cases of gynecomastia are common in three age populations: newborns, adolescents, and men older than 50 years old. Newborn gynecomastia occurs in about 60–90 percent of male babies and most cases resolve on their own. During adolescence, up to 70 percent of males are estimated to exhibit signs of gynecomastia. Senile gynecomastia is estimated to be present in 24–65 percent of men between the ages of fifty and eighty.

The prevalence of gynecomastia in men may have increased in recent years, but the epidemiology of the disorder is not fully understood. The use of anabolic steroids and exposure to chemicals that mimic estrogen in cosmetic products, organochlorine pesticides, and industrial chemicals have been suggested as possible factors driving this increase. According to the American Society of Plastic Surgeons, breast reduction surgeries to correct gynecomastia are becoming increasingly common. In 2006, there were 14,000 procedures of this type performed in the United States alone.

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.

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.

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.