Etiology
Primary hypogonadism
In primary hypogonadism (PH), the defect lies at the level of the testes ("testicular failure"). PH is associated with low testosterone and elevated gonadotropins (although Sertoli cell and seminiferous tubule function is typically lost first). While etiology cannot always be ascertained, common causes have been identified.
Aging: 1% to 2% of older men, with an incidence of around 0.2% per year.[5][14]
Klinefelter syndrome: the most common congenital cause of hypogonadism.[9][15] Klinefelter syndrome has a likely population prevalence of >5 per 10,000 men, but only 25% to 50% of men are diagnosed during their lifetime.[9] Most patients have 47,XXY genotype anomaly; mosaicism is also seen.[16]
Cryptorchidism (undescended testes): may also occur in congenital hypogonadotropic hypogonadism (e.g., Kallmann syndrome).[2]
Infection: orchitis related to mumps is the most common infection. HIV is a rare infectious cause.[9] Spermatogenesis is more affected than androgen production.
Drugs: alkylating agents, such as cyclophosphamide and chlorambucil, are the most notable examples. The seminiferous tubules are usually the main site of damage, although testosterone production can also be affected in later life. Ketoconazole also decreases testosterone production.[3] Males due to undergo therapy with alkylating agents should be given the option of sperm banking.[17]
Testicular trauma, torsion, or irradiation: also includes orchidectomy for testicular cancers, which are frequently metachronous.[9]
Varicocele: rarely causes hypogonadism, but does cause increased temperature and/or accumulation of tissue metabolites in the testes.[18]
Myotonic dystrophy: presence of CTG repeats has been associated with hypogonadism.[19]
Kennedy syndrome: associated with CTG repeats in the androgen receptor.[20]
Environmental toxins: including heavy metals, industrial chemicals, and pesticides.[21]
Substance use/misuse: excessive alcohol, tobacco, or cannabis consumption.[22]
Congenital adrenal hyperplasia with testicular adrenal rest tumors: can lead to primary gonadal failure.[23]
Secondary hypogonadism
In secondary (also known as central or hypogonadotropic) hypogonadism, the defect lies at the level of the hypothalamic-pituitary axis and is associated with low testosterone and low (or inappropriately normal) gonadotropins.
Combined pituitary hormone deficiency (CPHD): can present neonatally with complete pituitary dysfunction, or with progressive stepwise evolution during childhood or even adult life.[24]
Congenital hypogonadotropic hypogonadism (CHH): caused by a complete or partial failure of hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action, leading to a reduction in luteinizing hormone (LH) and follicle stimulating hormone (FSH) and failure to initiate and/or complete puberty.[2] Around 60% to 70% of affected individuals have nonreproductive congenital defects, of which anosmia (defining Kallmann syndrome) is by far the most common. Broadly, gene mutations that affect neuronal migration or targeting cause Kallmann syndrome, whereas those solely affecting the functional integrity of the GnRH secretory network cause normosmic CHH.[2]
Hyperprolactinemia: elevated prolactin level, from any cause, suppresses kisspeptin-mediated GnRH secretion.[4]
Sellar and parasellar lesions: cause compression of gonadotrophs. Includes pituitary and/or hypothalamic tumors, and pituitary apoplexy.
Drugs/substance use or misuse: opioids, cannabinoids, high-dose glucocorticoids (effect only seen in males), GnRH analogs, exogenous estrogens, exogenous androgens.[22]
Infiltrative disease: for example sarcoidosis, histiocytosis, hemochromatosis. Destruction of the gonadotrophs is considered to be the mechanism of action.[4][7]
Irradiation: damage to the pituitary gland or hypothalamus after cranial radiation therapy leading to decreased LH and FSH.[25]
Severe systemic illness: can suppress the hypothalamic-pituitary-gonadal axis; when the illness resolves, the axis usually recovers.[7]
Head injury: trauma (particularly military blast injury), surgery.
Cushing syndrome: reversible in patients in remission.[26]
Relative energy deficit: alterations in energy/nutritional balance, such as moderate to severe dietary restriction (e.g., anorexia nervosa) or ultra-endurance exercise (e.g., marathon running) may suppress the testosterone by suppressing central GnRH/LH pulses.[4][7]
Compensated hypogonadism
Defined biochemically as raised gonadotropins with normal testosterone levels, and occurs in around 10% of older men.[5] It may progress to frank hypogonadism over time, as typically occurs in Klinefelter syndrome, but there is no consensus on whether it should be treated.[5][14] The presence of characteristic clinical features such as anemia, low bone density, or refractory sexual dysfunction should prompt serious consideration of treatment.[2]
Late-onset hypogonadism
Defined as decreased sexual interest, decreased morning erections, and erectile dysfunction, in combination with testosterone deficiency.[5][6] Late-onset hypogonadism is associated with advancing age and may result in significant detriment to quality of life.[2][27][28] Must be carefully distinguished from nongonadal illness.
Pathophysiology
Pathology at any level of the hypothalamic-pituitary-gonadal axis may result in hypogonadism.[3] The causes include genetic diseases, head or testicular trauma, tumors, radiation injury, alkylating agents, hyperprolactinemia, and infiltrative diseases. Determining the etiology and location of injury to the hypothalamic-pituitary-gonadal axis is important because the investigation, prognosis, and treatment options vary with these factors.
Primary hypogonadism (PH)
PH is an end-organ disease. It occurs due to pathology of either Leydig cells or seminiferous tubules or both. Injury to Leydig cells results in decreased testosterone production, while seminiferous tubule involvement results in decreased or absent spermatogenesis. The majority of the conditions causing testicular injury predominantly involve tubules, with Leydig cell function usually declining later in the natural history. Gonadotropins are elevated due to loss of negative feedback from Leydig cell (testosterone, insulin-like factor 3 [INSL3]) and Sertoli cell (anti-Müllerian hormone [AMH], inhibin B) hormones. Progressive PH is associated with increased risk for type 2 diabetes mellitus, irrespective of cause.[2]
Secondary hypogonadism
Causes of secondary (also known as central or hypogonadotropic) hypogonadism include genetic mutations (resulting in developmentally defective GnRH secretion or action), hyperprolactinemia (causing suppression of GnRH), or destruction/compression of the gonadotrophs by parasellar tumor or hemorrhagic infarction of tumor (apoplexy), trauma, and infiltrative diseases.[3] Chronic diseases such as metabolic syndrome and diabetes can lead to secondary hypogonadism.[29] The underlying pathophysiologic mechanism of diabetes, obesity, and metabolic syndrome to the resultant hypogonadism is not fully known, but may include increased insulin resistance, inflammatory mediators, and decreased insulin and leptin signaling in the central nervous system.[30]
Obesity is associated with low testosterone levels, but this is frequently an artefact due to low sex hormone binding globulin levels and most obese men do not have hypogonadal clinical features. However, proinflammatory adipocytokines (produced by adipose tissue) may inhibit the hypothalamic-pituitary-testicular axis, impairing testosterone secretion.[29]
In secondary hypogonadism, gonadotropin levels are decreased or inappropriately normal, and this results in decreased testicular stimulation, causing decreased spermatogenesis and androgen production. Prolonged secondary hypogonadism leads to testicular atrophy.
Classification
Clinical classification
Hypogonadism is broadly classified as primary or secondary, according to the site of physiologic dysfunction.[3]
Primary hypogonadism: dysfunction of the testes resulting in failure of spermatogenesis and/or testosterone production.
Secondary (also known as central or hypogonadotropic) hypogonadism: dysfunction of the hypothalamus and/or the pituitary gland causing failure to secrete GnRH (or LH and FSH). This is the only form of male infertility that is treatable with hormone (FSH and human chorionic gonadotropin) replacement.
Each type of hypogonadism is then further classified by whether the cause is congenital or acquired.[3][4]
Late-onset hypogonadism is defined as decreased sexual interest, decreased morning erections, and erectile dysfunction, in combination with testosterone deficiency.[5][6] Must be carefully distinguished from symptoms attributable to nongonadal illnesses.[2]
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