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Hypogonadism
Hypogonadism
Hypogonadism
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Hypogonadism
Other namesInterrupted stage 1 puberty, hypoandrogenism, hypoestrogenism
SpecialtyEndocrinology

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estrogen (e.g., estradiol) as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

Hypogonadism, commonly referred to by the symptom "low testosterone" or "low T", can also decrease other hormones secreted by the gonads including progesterone, DHEA, anti-Müllerian hormone, activin, and inhibin. Sperm development (spermatogenesis) and release of the egg from the ovaries (ovulation) may be impaired by hypogonadism, which, depending on the degree of severity, may result in partial or complete infertility.

In January 2020, the American College of Physicians issued clinical guidelines for testosterone treatment in adult men with age-related low levels of testosterone. The guidelines are supported by the American Academy of Family Physicians. The guidelines include patient discussions regarding testosterone treatment for sexual dysfunction; annual patient evaluation regarding possible notable improvement and, if none, to discontinue testosterone treatment; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar; and, testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended.[1][2]

Classification

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Main articles: Hypergonadotropic hypogonadism, Hypogonadotropic hypogonadism, and Isolated hypogonadotropic hypogonadism

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 (hyper-gonatropic hypogonadism); whereas in secondary hypogonadism, both are normal or low, suggesting the problem is in the brain (hypo-gonatropic hypogonadism).[citation needed]

Affected system

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Primary or secondary

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Congenital vs. acquired

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Hormones vs. fertility

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Hypogonadism can involve just hormone production or just fertility, but most commonly involves both.[citation needed]

  • 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.

Other

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Hypogonadism can occur in other conditions, like Prader–Willi syndrome.[citation needed]

Signs and symptoms

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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 men, it causes impaired muscle and body hair development, gynecomastia, decreased height, erectile dysfunction, and sexual difficulties. If hypogonadism is caused by a disorder of the central nervous system (e.g., a brain tumor), then this is known as central hypogonadism. Signs and symptoms of central hypogonadism may involve headaches, impaired vision, double vision, milky discharge from the breast, and symptoms caused by other hormone problems.[6]

Hypogonadotrophic hypogonadism

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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.[citation needed]

Diagnosis

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Women

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Testing serum LH and FSH levels are often used to assess hypogonadism in women, particularly when menopause is believed to be happening. These levels change during a woman's normal menstrual cycle, so the history of having ceased menstruation coupled with high levels aids the diagnosis of being menopausal. Commonly, the post-menopausal woman is not called hypogonadal if she is of typical menopausal age. Contrast with a young woman or teen, who would have hypogonadism rather than menopause. This is because hypogonadism is an abnormality, whereas menopause is a normal change in hormone levels. In any case, the LH and FSH levels will rise in cases of primary hypogonadism or menopause, while they will be low in women with secondary or tertiary hypogonadism.[7]

Hypogonadism is often discovered during the evaluation of delayed puberty, but ordinary delay, which eventually results in normal pubertal development, wherein reproductive function is termed constitutional delay. It may be discovered during an infertility evaluation in either men or women.[8]

Men

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Low testosterone can be identified through a simple blood test performed by a laboratory, ordered by a health care provider. Blood for the test must be taken in the morning hours, when levels are highest, as levels can drop by as much as 13% during the day and all normal reference ranges are based on morning levels.[9][10]

Normal total testosterone levels depend on the man's age but generally range from 240 to 950 ng/dL (nanograms per deciliter) or 8.3–32.9 nmol/L (nanomoles per liter).[11] According to American Urological Association, the diagnosis of low testosterone can be supported when the total testosterone level is below 300 ng/dl.[12] Some men with normal total testosterone have low free or bioavailable testosterone levels which could still account for their symptoms. Men with low serum testosterone levels should have other hormones checked, particularly luteinizing hormone to help determine why their testosterone levels are low and help choose the most appropriate treatment (most notably, testosterone is usually not appropriate for secondary or tertiary forms of male hypogonadism, in which the LH levels are usually reduced).[citation needed]

Treatment is often prescribed for total testosterone levels below 230 ng/dL with symptoms.[13] If the serum total testosterone level is between 230 and 350 ng/dL, free or bioavailable testosterone should be checked as they are frequently low when the total is marginal.[citation needed]

The standard range given is based on widely varying ages and, given that testosterone levels naturally decrease as humans age, age-group specific averages should be taken into consideration when discussing treatment between doctor and patient.[14] In men, testosterone falls approximately 1 to 3 percent each year.[15]

Blood testing

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A position statement by the Endocrine Society expressed dissatisfaction with most assays for total, free, and bioavailable testosterone.[16] In particular, research has questioned the validity of commonly administered assays of free testosterone by radioimmunoassay.[16] The free androgen index, essentially a calculation based on total testosterone and sex hormone-binding globulin levels, is the worst predictor of free testosterone levels and should not be used.[17] Measurement by equilibrium dialysis or mass spectroscopy is generally required for accurate results, particularly for free testosterone which is normally present in very small concentrations.[citation needed]

Screening

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Screening males who do not have symptoms of hypogonadism is not recommended as of 2018.[18]

Treatment

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Male primary or hypergonadotropic hypogonadism is often treated with testosterone replacement therapy if they are not trying to conceive.[13]

In short- and medium-term testosterone replacement therapy the risk of cardiovascular events (including strokes and heart attacks and other heart diseases) is not increased. The long-term safety of the therapy is not known yet.[19][20] Side effects can include an elevation of hematocrit to levels that require blood withdrawal (phlebotomy) to prevent complications from excessively thick blood. Gynecomastia (growth of breasts in men) sometimes occurs. Finally, some physicians worry that obstructive sleep apnea may worsen with testosterone therapy, and should be monitored.[21]

While historically, men with prostate cancer risk were warned against testosterone therapy, that has shown to be a myth.[22]

Another treatment for hypogonadism is human chorionic gonadotropin (hCG).[23] This stimulates the LH receptor, thereby promoting testosterone synthesis. This will not be effective in men whose testes simply cannot synthesize testosterone anymore (primary hypogonadism), and the failure of hCG therapy is further support for the existence of true testicular failure in a patient. It is particularly indicated in men with hypogonadism who wish to retain their fertility, as it does not suppress spermatogenesis (sperm production) as testosterone replacement therapy does.[citation needed]

For both men and women, an alternative to testosterone replacement is low-dose clomifene treatment, which can stimulate the body to naturally increase hormone levels while avoiding infertility and other side effects that can result from direct hormone replacement therapy.[24] Clomifene blocks estrogen from binding to some estrogen receptors in the hypothalamus, thereby causing an increased release of gonadotropin-releasing hormone and subsequently LH from the pituitary. Clomifene is a selective estrogen receptor modulator (SERM). Generally, clomifene does not have adverse effects at the doses used for this purpose.

Androgen replacement therapy formulations and dosages used in men
Route Medication Major brand names Form Dosage
Oral Testosteronea – Tablet 400–800 mg/day (in divided doses)
Testosterone undecanoate Andriol, Jatenzo Capsule 40–80 mg/2–4× day (with meals)
Methyltestosteroneb Android, Metandren, Testred Tablet 10–50 mg/day
Fluoxymesteroneb Halotestin, Ora-Testryl, Ultandren Tablet 5–20 mg/day
Metandienoneb Dianabol Tablet 5–15 mg/day
Mesteroloneb Proviron Tablet 25–150 mg/day
Sublingual Testosteroneb Testoral Tablet 5–10 mg 1–4×/day
Methyltestosteroneb Metandren, Oreton Methyl Tablet 10–30 mg/day
Buccal Testosterone Striant Tablet 30 mg 2×/day
Methyltestosteroneb Metandren, Oreton Methyl Tablet 5–25 mg/day
Transdermal Testosterone AndroGel, Testim, TestoGel Gel 25–125 mg/day
Androderm, AndroPatch, TestoPatch Non-scrotal patch 2.5–15 mg/day
Testoderm Scrotal patch 4–6 mg/day
Axiron Axillary solution 30–120 mg/day
Androstanolone (DHT) Andractim Gel 100–250 mg/day
Rectal Testosterone Rektandron, Testosteronb Suppository 40 mg 2–3×/day
Injection (IMTooltip intramuscular injection or SCTooltip subcutaneous injection) Testosterone Andronaq, Sterotate, Virosterone Aqueous suspension 10–50 mg 2–3×/week
Testosterone propionateb Testoviron Oil solution 10–50 mg 2–3×/week
Testosterone enanthate Delatestryl Oil solution 50–250 mg 1x/1–4 weeks
Xyosted Auto-injector 50–100 mg 1×/week
Testosterone cypionate Depo-Testosterone Oil solution 50–250 mg 1x/1–4 weeks
Testosterone isobutyrate Agovirin Depot Aqueous suspension 50–100 mg 1x/1–2 weeks
Testosterone phenylacetateb Perandren, Androject Oil solution 50–200 mg 1×/3–5 weeks
Mixed testosterone esters Sustanon 100, Sustanon 250 Oil solution 50–250 mg 1×/2–4 weeks
Testosterone undecanoate Aveed, Nebido Oil solution 750–1,000 mg 1×/10–14 weeks
Testosterone buciclatea – Aqueous suspension 600–1,000 mg 1×/12–20 weeks
Implant Testosterone Testopel Pellet 150–1,200 mg/3–6 months
Notes: Men produce about 3 to 11 mg of testosterone per day (mean 7 mg/day in young men). Footnotes: a = Never marketed. b = No longer used and/or no longer marketed. Sources: See template.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hypogonadism

View on Grokipedia
from Grokipedia
Hypogonadism is a medical condition characterized by the diminished or absent function of the gonads, the reproductive glands that produce sex , resulting in insufficient levels of testosterone in males and or progesterone in females. This deficiency disrupts normal reproductive and secondary sexual development, often leading to , if onset occurs before , or various systemic effects in adults depending on the timing and severity. The condition is broadly classified into primary hypogonadism, where the defect lies directly in the gonads (testes or ovaries), and secondary hypogonadism, stemming from dysfunction in the or that fails to adequately stimulate gonadal production. Primary forms are marked by elevated levels of s (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) due to lack of from low sex hormones, whereas secondary forms show low or inappropriately normal levels. A less common tertiary category may refer specifically to hypothalamic issues. Causes of primary hypogonadism include genetic abnormalities such as in males or in females, as well as acquired factors like testicular or ovarian trauma, infections (e.g., mumps orchitis), , , or surgical removal of the gonads. Secondary hypogonadism can arise from pituitary tumors, , infiltrative diseases like hemochromatosis, or genetic conditions such as , which impairs (GnRH) secretion. In females, represents the most prevalent natural cause of hypogonadism, typically occurring around age 50 due to depletion. Symptoms manifest differently based on , age at onset, and affected but commonly include reproductive issues like and low across both sexes. In adult males, notable signs are , reduced spontaneous erections, fatigue, decreased muscle mass and strength, increased body fat, , and . For females, symptoms often involve amenorrhea or oligomenorrhea, hot flashes, vaginal leading to , loss of breast tissue, and reduced density. If untreated in children or adolescents, hypogonadism can cause delayed or absent , , and underdeveloped secondary sexual characteristics. Diagnosis relies on clinical evaluation combined with laboratory testing, including morning serum measurements of total testosterone (below 300 ng/dL on two occasions for males) or estradiol/FSH/LH levels for females, alongside assessment of symptoms. Additional tests may include , scans, or MRI of the pituitary/ to identify underlying causes. Treatment primarily involves tailored to the patient's sex and goals, such as testosterone supplementation via injections, gels, or patches for males to improve energy, , and , though it may not restore . In females, estrogen-progestin combinations address menopausal or premature ovarian insufficiency symptoms, with therapy considered for preservation in secondary cases. Management of underlying etiologies, such as tumor resection or lifestyle interventions for obesity-related secondary hypogonadism, is also essential to optimize outcomes and prevent complications like or .

Overview

Definition

Hypogonadism is defined as a condition characterized by diminished functional activity of the gonads, the testes in males and the ovaries in females, resulting in reduced production of sex hormones such as and , as well as impaired . This leads to inadequate levels of these hormones, which are essential for reproductive and overall physiological functions. The condition arises from disruptions in the hypothalamic-pituitary-gonadal (HPG) axis, the primary regulatory system for gonadal function. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the gland to release (FSH) and (LH). These gonadotropins, in turn, act on the gonads to promote the synthesis and secretion of sex steroids (testosterone in males and /progesterone in females) and the production of gametes ( in males and oocytes in females). Sex hormones play critical physiological roles, including the initiation and progression of , the development of secondary such as in males and in females, the maintenance of reproductive capacity through and fertilization, and influences on , bone density, and muscle mass. In males, testosterone drives and , while in females, supports ovarian follicle maturation and uterine preparation for . These hormones also exert broader effects, modulating cardiovascular health, immune responses, and energy . The term hypogonadism has been used since the early to describe gonadal insufficiency, with significant milestones including the identification of gonadotropins in the 1920s, which elucidated the hormonal control of gonadal function. The condition was recognized for centuries prior through clinical observations of eunuchs and those with , but modern understanding emerged with advances in during this period. Hypogonadism is broadly classified into primary (gonadal) and secondary (central) types, though detailed distinctions are beyond this overview.

Epidemiology

Hypogonadism affects a significant portion of the population, with varying by sex, age, and underlying . In males, the of symptomatic hypogonadism ranges from 2.1% to 5.7% among those aged 40 to 79 years, though symptomatic cases in men in their 40s are much rarer than biochemical low testosterone alone, often less than 1–5% in this age group. , characterized by age-related testosterone decline, increases with advancing age, affecting approximately 12% of men aged 50 years and up to 30% of those aged 70 years. In females, global data are less comprehensive, but congenital forms such as occur in approximately 1 to 10 per 100,000 live births, more common in males with a male-to-female ratio of approximately 3:1 to 5:1. Hypogonadism contributes substantially to , particularly through mechanisms like , which accounts for about 25% of cases. Specific genetic syndromes illustrate higher incidence rates within subgroups. , a common cause of primary hypogonadism in males, has a prevalence of 1 in 500 to 1,000 newborn males. , leading to primary hypogonadism in females, affects approximately 1 in 2,000 to 2,500 female live births. Demographic patterns show age-related declines in gonadal function, often termed andropause in men and overlapping with in women, where hypogonadism exacerbates postmenopausal symptoms. Sex differences influence clinical focus, with male cases emphasizing hormone replacement for metabolic effects and female cases prioritizing fertility preservation due to ovulatory disruptions. Geographic variations exist, with lower serum testosterone levels observed in some populations; for instance, Asian men in certain regions exhibit up to 20% higher testosterone than others, potentially linked to environmental factors. Regions with , such as parts of and , report higher rates of secondary hypogonadism due to disrupting the thyroid-gonadal axis. Key risk factors include , , and chronic illnesses, which amplify prevalence. Among men, hypogonadism rates reach 32% to 64%, with up to 75% in severe (BMI >40 kg/m²). In men with , prevalence is 25% to 40%, often manifesting as secondary hypogonadism. Chronic conditions like and further elevate risk through direct gonadal impairment or hypothalamic-pituitary disruption. Post-2020 data indicate associations between infection and transient hypogonadism, with hospitalized men showing low testosterone levels linked to severe disease outcomes and persistent effects in some long-COVID cases. Diagnosis trends reflect improved screening and awareness, leading to rising reported cases, particularly in aging populations. The incidence of diagnosed male hypogonadism has increased 1.4-fold from 2001-2009 to 2010-2017, driven by better recognition of late-onset forms. Projections estimate a substantial rise by 2030, with the global male hypogonadism market expanding from USD 3.41 billion in 2025 to USD 4.36 billion, attributable to demographic aging where individuals over 60 are expected to comprise a larger share.

Classification

Primary versus secondary

Hypogonadism is classified into primary and secondary forms based on the site of dysfunction within the hypothalamic-pituitary-gonadal (HPG) axis. Primary hypogonadism results from direct failure of the gonads, leading to inadequate production of sex hormones despite elevated levels of (FSH) and (LH). This condition is characterized by an end-organ defect where the testes in males or ovaries in females cannot respond appropriately to stimulation. Examples include damage to testicular or ovarian tissue that impairs hormone synthesis and . In contrast, secondary hypogonadism arises from dysfunction in the or , resulting in deficient secretion and consequently low levels. Here, FSH and LH levels are low or inappropriately normal relative to the reduced sex hormones, reflecting a central defect in the HPG axis. A subtype of secondary hypogonadism is , where the lack of (GnRH) from the hypothalamus disrupts the entire downstream signaling. The primary distinction between these forms lies in whether the defect is at the end-organ (gonadal) level or central (hypothalamic-pituitary) level, which guides diagnostic classification. A typical decision process begins with confirming low levels, followed by measuring FSH and LH: elevated gonadotropins indicate primary hypogonadism, while low or normal levels point to secondary. If secondary is suspected, further evaluation may assess pituitary function or hypothalamic integrity, though this classification focuses on the initial anatomical localization rather than detailed . Clinically, primary hypogonadism is often irreversible due to inherent gonadal damage, necessitating lifelong hormone replacement to manage symptoms. Secondary hypogonadism, however, may be potentially treatable if the underlying central cause can be addressed, such as through restoration of pituitary function. This differentiation influences and therapeutic strategies, emphasizing the importance of precise HPG axis evaluation. The classification of hypogonadism into primary and secondary categories evolved in the mid-20th century, shifting from purely descriptive terms like "hypoleydigism" to a framework based on HPG axis , as articulated in early endocrine discussions around 1941. This HPG-centric approach, refined with advancing knowledge of gonadotropins and feedback mechanisms, provided a more mechanistic understanding by the 1950s.

Congenital versus acquired

Hypogonadism is classified as congenital when it is present from birth, typically arising from genetic or developmental defects that disrupt the hypothalamic-pituitary-gonadal axis, leading to failure of and manifestations such as delayed or absent pubertal development. In contrast, acquired hypogonadism develops after birth due to postnatal factors including injury, infectious diseases, chronic illnesses, or age-related decline, and it may sometimes superimpose on underlying congenital conditions. The primary differences between congenital and acquired forms lie in their timing and impact on development: congenital hypogonadism affects growth, sexual maturation, and from early life, often resulting in preserved but disrupted pubertal progression, whereas acquired hypogonadism typically spares initial development and emerges later, potentially altering established reproductive function. For instance, congenital primary hypogonadism may present with conditions like anorchia, highlighting the overlap with axis-level classifications. Congenital hypogonadism is relatively rare, with an estimated incidence of 1 to 10 per 100,000 live births for hypogonadotropic forms, accounting for a small proportion—less than 5 per 10,000 males overall—among diagnosed cases. Acquired forms predominate in adulthood, particularly due to aging, with studies indicating that approximately 40% of men over 45 years exhibit , rising to 20% in those over 60 and 50% over 80, where nearly all cases are acquired rather than congenital. Diagnosis of congenital hypogonadism often relies on clues such as family history of similar disorders or associated congenital anomalies, while acquired cases are typically identified through timelines of trauma, illness, or exposure preceding symptom onset.

Hypogonadotropic versus hypergonadotropic

, also known as secondary hypogonadism, is characterized by low or inappropriately normal levels of (FSH) and (LH) due to dysfunction in the or , leading to inadequate stimulation of the gonads despite their intrinsic normality. In this condition, the absence of central (GnRH) secretion or pituitary responsiveness results in reduced gonadal hormone production, such as testosterone in males or in females, without compensatory elevation in gonadotropins. This central defect disrupts the hypothalamic-pituitary-gonadal (HPG) axis upstream of the gonads. In contrast, , or primary hypogonadism, features elevated FSH and LH levels arising from gonadal failure or resistance, where the testes or ovaries cannot adequately produce sex steroids or respond to stimulation. The resulting deficiency in sex hormones fails to provide sufficient negative feedback to the pituitary, causing persistent hypersecretion of FSH and LH in an attempt to compensate for the gonadal insufficiency. Common causes include genetic disorders like in males or in females, as well as acquired damage from toxins or infections affecting gonadal tissue. The distinction between these forms hinges on the mechanism within the HPG axis, where sex steroids (e.g., testosterone and ) and gonadal peptides like inhibin normally suppress GnRH release from the and secretion from the pituitary to maintain . In , the feedback loop is impaired at the central level, preventing release even if inhibin levels remain low due to understimulation of the gonads; conversely, in , gonadal dysfunction abolishes this feedback, leading to unchecked elevation as the pituitary perceives a lack of inhibitory signals from deficient sex steroids and inhibin. This regulatory imbalance underscores how hypogonadotropic forms often stem from hypothalamic-pituitary issues, while hypergonadotropic types reflect downstream gonadal pathology. Clinical subtypes illustrate these differences: represents a congenital hypogonadotropic form, caused by genetic mutations impairing GnRH neuron migration and often associated with , resulting in isolated deficiency from birth. On the hypergonadotropic side, chemotherapy-induced azoospermia or ovarian failure exemplifies an acquired subtype, where alkylating agents damage germ cells and steroidogenic tissues, leading to irreversible or partially reversible gonadal hypofunction with elevated gonadotropins. Prognostically, is frequently more amenable to reversal or management, particularly if the underlying central cause (e.g., a pituitary tumor or nutritional deficiency) is treatable, allowing restoration of and production through targeted interventions. , however, tends to involve more structural gonadal damage, rendering it less reversible and often requiring lifelong replacement, though preservation options may mitigate long-term impacts in select cases.

Causes

Genetic and developmental causes

Hypogonadism can arise from genetic causes, including chromosomal abnormalities and single-gene mutations that disrupt gonadal development or function. Chromosomal disorders such as , characterized by a 47,XXY , lead to primary hypogonadism in males through testicular dysgenesis, resulting in elevated levels and low testosterone. Similarly, , with a 45,XO , causes in females due to ovarian dysgenesis and accelerated , often presenting with primary amenorrhea. Single-gene mutations also contribute significantly; for instance, mutations in the ANOS1 gene (formerly KAL1), which encodes anosmin-1, underlie X-linked , combining with due to impaired (GnRH) neuronal migration. Developmental anomalies during embryogenesis further predispose individuals to hypogonadism. , the failure of testicular descent, is associated with genetic factors such as mutations in the INSL3 or RXFP2 genes, which regulate gubernacular development, and can lead to primary hypogonadism from impaired and testosterone production later in life. , or Mayer-Rokitansky-Küster-Hauser syndrome, involves congenital absence of the uterus and upper vagina, and in rare cases overlaps with , resulting in primary ovarian failure and . (CAH), primarily due to CYP21A2 mutations, causes androgen excess that suppresses the hypothalamic-pituitary-gonadal axis, leading to , particularly in untreated cases. Inheritance patterns vary across these etiologies, reflecting the genetic heterogeneity of hypogonadism. is seen in , caused by mutations in the AR gene encoding the , which results in female external genitalia in 46,XY individuals despite normal testosterone production, effectively causing functional hypogonadism. Autosomal recessive patterns occur in conditions like mutations in the GNRHR gene, impairing GnRH receptor signaling and leading to isolated , while autosomal dominant inheritance is exemplified by FGFR1 mutations in variants. At the molecular level, inactivating mutations in the FSHR gene, which encodes the , disrupt follicular development and cause premature ovarian failure with hypergonadotropic features in females. Recent genomic studies in the 2020s have expanded understanding through next-generation sequencing, identifying over 50 genes associated with , including novel variants in PROK2, CHD7, and SEMA3A that affect GnRH neuron migration or secretion. These advances highlight oligogenic contributions, where multiple gene variants interact to produce the , enabling more precise and targeted therapies.

Acquired and environmental causes

Acquired hypogonadism arises from factors that develop after birth and disrupt the hypothalamic-pituitary-gonadal (HPG) axis, often through damage to the gonads, pituitary, or . Medical conditions such as chronic illnesses can lead to primary or secondary hypogonadism; for instance, hemochromatosis causes that deposits in the testes or pituitary, impairing gonadal function and resulting in low testosterone levels. Similarly, infection may induce hypogonadism via direct testicular damage from opportunistic infections or through secondary effects like chronic inflammation affecting the pituitary, with a of approximately 26% in affected men. Endocrine disorders, including prolactinomas, elevate levels that suppress (GnRH) secretion, leading to secondary hypogonadism; treatment with dopamine agonists often reverses this effect. Iatrogenic causes are common in cancer therapy and surgical interventions. to the or can destroy Leydig cells or pituitary tissue, causing primary or secondary hypogonadism, respectively, with risks increasing with doses above 12-15 Gy to the gonads. , particularly alkylating agents like , induces dose-dependent gonadal toxicity by damaging germ cells and steroidogenic cells, leading to and testosterone deficiency in up to 50% of survivors. Surgical procedures, such as bilateral for or in women, directly remove gonadal tissue, resulting in immediate and permanent hypogonadism. Environmental and lifestyle factors contribute to hypogonadism through endocrine disruption or metabolic changes. Exposure to endocrine-disrupting chemicals (EDCs) like in plastics and (BPA) in consumer products mimics or inhibits synthesis, altering HPG axis signaling and reducing testosterone production in animal models and human cohorts. Obesity promotes hypogonadism by increasing aromatase activity, which converts testosterone to , and via elevated levels that suppress hypothalamic GnRH pulsatility; meta-analyses indicate obese men have 30-50% lower free testosterone compared to normal-weight peers. Chronic opioid use, including prescription painkillers, inhibits GnRH secretion at the hypothalamic level, causing central hypogonadism in 50-70% of long-term users, with effects reversible upon discontinuation in many cases. Aging-related hypogonadism, often termed (LOH), involves a gradual decline in testosterone levels starting around age 40, at a rate of about 1-2% per year, due to reduced function and hypothalamic sensitivity. This affects 2-6% of men over 40, with symptoms emerging when levels fall below 300 ng/dL, though requires both biochemical and clinical correlation. Emerging evidence links to hypogonadism, with acute associated with transient testosterone reductions of up to 40% due to inflammatory cytokines suppressing the HPG axis or direct viral effects on testicular ACE2 receptors. Post-recovery studies from 2020-2024 report persistent hypogonadism in 20-30% of male survivors, potentially from or ongoing immune dysregulation, highlighting the need for endocrine follow-up in affected individuals.

Pathophysiology

Mechanisms in primary hypogonadism

Primary hypogonadism arises from direct failure of the gonads to produce adequate sex hormones and gametes, leading to disruptions in both steroidogenesis and . In males, this typically involves damage to Leydig cells, which are responsible for testosterone synthesis, resulting in reduced serum testosterone levels, often below 300 ng/dL, a threshold indicative of deficiency in primary cases. Concurrently, impairment diminishes inhibin B production and , contributing to . In females, analogous damage affects granulosa and theca cells in the ovaries, impairing estrogen and progesterone synthesis, which disrupts menstrual cycles and . The core hormonal mechanism in primary hypogonadism is the failure of to the hypothalamic-pituitary axis. Normally, gonadal steroids (testosterone in males, and progesterone in females) and inhibins suppress the release of gonadotropins— (LH) and (FSH)—from the pituitary. In primary hypogonadism, the absence of these suppressive signals leads to elevated LH and FSH levels, a hallmark of , as the pituitary compensates for the perceived deficiency. This feedback failure also halts production, with in males and amenorrhea in females due to depleted reserves. At the cellular level, primary hypogonadism often involves pathological processes such as and within gonadal tissues. Toxins, , or can induce (apoptosis) in germ cells and steroid-producing cells, accelerating gonadal depletion. In autoimmune forms, such as in females, lymphocytic infiltration leads to and scarring of ovarian stroma, further compromising follicular development. Sex-specific changes are prominent: in males, atrophy predominates, with hyalinization and loss of tubular architecture due to progressive germ cell loss and dysfunction. In females, accelerated —where primordial follicles undergo premature degeneration—underlies the rapid decline in , often resulting in streak ovaries with fibrous replacement. These mechanisms collectively underscore the end-organ nature of primary hypogonadism, distinct from central defects.

Mechanisms in secondary hypogonadism

Secondary hypogonadism arises from disruptions in the hypothalamic-pituitary axis, leading to deficient (GnRH) secretion or impaired pituitary production, which in turn fails to adequately stimulate the gonads. Unlike primary hypogonadism, the gonadal tissue remains responsive to stimulation, but the central regulatory signals are compromised, resulting in low levels of (LH) and (FSH) alongside reduced production. This central failure disrupts the pulsatile nature of GnRH release, which is essential for normal gonadal function. Hypothalamic dysfunction is a primary mechanism in secondary hypogonadism, characterized by GnRH deficiency due to impaired from GnRH neurons in the . This pulsatile failure can stem from structural lesions such as tumors (e.g., craniopharyngiomas or hypothalamic hamartomas) that compress GnRH-producing neurons or from functional disruptions like , which suppresses GnRH pulse frequency through elevated levels interfering with hypothalamic signaling. In congenital forms like , GnRH neurons fail to migrate properly during development, leading to isolated GnRH deficiency. Acquired causes, including severe illness or nutritional deficits, further exemplify how external stressors can reversibly halt pulsatile GnRH output, preventing downstream LH and FSH surges. Pituitary defects contribute significantly by causing loss or dysfunction of gonadotroph cells responsible for LH and FSH synthesis and release. Ischemic necrosis, as seen in following postpartum hemorrhage, leads to selective destruction of pituitary lactotrophs and gonadotrophs, resulting in panhypopituitarism that includes . Traumatic injury, , or infiltrative diseases like can similarly damage gonadotrophs, reducing gonadotropin output despite intact hypothalamic input. Additionally, hyperprolactinemia from prolactinomas or medications inhibits GnRH action at the pituitary level by downregulating gonadotroph responsiveness, thereby suppressing LH and FSH secretion and inducing a state of functional hypogonadism. The feedback loops in the hypothalamic-pituitary-gonadal (HPG) axis remain intact in secondary hypogonadism, but inadequate central stimulation leads to low gonadotropin levels despite reduced sex hormone feedback. Normally, low gonadal steroids should disinhibit the hypothalamus and pituitary to increase GnRH and gonadotropin release; however, in secondary forms, this loop fails due to upstream defects, maintaining low LH and FSH even as estrogen or testosterone levels drop. This results in preserved gonadal potential, as evidenced by responsiveness to exogenous gonadotropins, but chronic understimulation causes secondary atrophy or impaired function over time. Neuroendocrine integration plays a crucial role, with serving as a key upstream regulator of GnRH neurons in the HPG axis. , produced by neurons in the arcuate and anteroventral periventricular nuclei, stimulates GnRH release in a pulsatile manner, integrating metabolic and reproductive signals. Disruptions in energy balance, such as in , suppress expression through deficiency and elevated glucocorticoids, thereby inhibiting GnRH pulsatility and leading to hypogonadotropic states. This metabolic sensing ensures reproductive suppression during negative energy balance to prioritize survival, highlighting 's role as a metabolic for . Chronic effects of these central disruptions often manifest as reversible suppression, particularly in (FHA), where psychosocial stress, excessive exercise, or leads to sustained GnRH inhibition. In FHA, the suppression is adaptive and non-structural, allowing recovery of HPG function upon restoration of energy balance and stress reduction, with resumption of menses and in many cases. This reversibility underscores the plasticity of the central axis, distinguishing it from irreversible genetic or destructive pathologies.

Signs and Symptoms

In males

Hypogonadism in males manifests through a range of symptoms related to , which can present during or in adulthood, affecting physical, sexual, and metabolic functions. In cases of pubertal delay, typically due to onset before or during , males may exhibit absent or incomplete development of secondary , such as lack of facial and growth, failure of voice deepening, and delayed or absent testicular enlargement by age 14. Additionally, these individuals often experience slow overall growth, , and , where breast tissue enlarges disproportionately. The absence of these pubertal changes stems from insufficient testosterone production, leading to a eunuchoid body habitus with long limbs relative to trunk length. For adult-onset hypogonadism, symptoms primarily arise from progressive and include fatigue, reduced energy levels, and , which involves difficulty achieving or maintaining an . Reduced and diminished are common, alongside loss of muscle mass and strength, contributing to decreased physical performance. In cases of transient hypogonadism secondary to critical illness or severe acute conditions, these symptoms, particularly reduced libido and erectile dysfunction, are typically temporary and improve as testosterone levels recover toward normal after the acute phase and hospital discharge, which may take weeks to months. Reduced body and facial hair growth is also common due to decreased androgen activity. Additionally, low testosterone may lead to slowed progression of male pattern baldness (reduced hairline recession) in genetically susceptible individuals by decreasing levels of dihydrotestosterone (DHT), the primary driver of androgenetic alopecia. Long-term effects also encompass an increased risk of due to reduced density from low testosterone's impact on . Reproductive symptoms are prominent, with infertility resulting from impaired spermatogenesis, often presenting as azoospermia (complete absence of sperm in semen) or oligospermia (low sperm count). In primary hypogonadism, testes are typically small and firm, measuring less than 4 mL in volume, reflecting direct gonadal failure. These changes lead to reduced fertility potential, though secondary hypogonadism may allow partial sperm production if the underlying hypothalamic-pituitary issue is addressed. Metabolically, male hypogonadism is associated with increased fat mass, particularly visceral adiposity, which exacerbates and contributes to . This shift promotes higher risks of through impaired glucose tolerance and elevated free fatty acid levels. Mood disturbances, such as depression, anxiety, and , as well as sleep disturbances including insomnia, are also frequent, linked to low testosterone's role in regulation, mood stabilization, and sleep quality. The severity of symptoms in males is often graded using tools like the , a validated assessing 17 items across psychological, somato-vegetative, and sexual domains to quantify symptom clusters and monitor testosterone deficiency impact. Low testosterone levels, typically below 300 ng/dL, combined with moderate or severe AMS scores (≥37 points), indicate clinically significant hypogonadism requiring intervention.

In females

In females, hypogonadism manifests primarily through deficiency, leading to disruptions in reproductive, skeletal, cardiovascular, and psychological health. During , affected individuals often experience primary amenorrhea, characterized by the absence of by age 15 or 16, alongside a lack of secondary sexual characteristics such as and growth. This is particularly evident in conditions like , where ovarian dysgenesis results in due to impaired growth hormone-insulin-like growth factor-1 axis function and deficiency. In adult women, hypogonadism commonly presents as secondary amenorrhea, with cessation of menstrual cycles due to and failure of follicular development. deficiency also causes vasomotor symptoms like hot flashes and , as well as genitourinary issues including vaginal dryness and , which contribute to and reduced sexual function. arises from chronic , preventing and implantation despite potential preservation of other ovarian functions in secondary forms. Skeletal complications are prominent, with estrogen deficiency accelerating and leading to , a condition marked by reduced mineral density and increased fracture risk, particularly in the spine, , and . This is exacerbated in premature hypogonadism, where bone loss begins earlier than in natural , heightening long-term morbidity. Cardiovascular risks are elevated due to estrogen deficiency, which removes protective effects on profiles and vascular integrity, promoting and progression. Studies indicate that women with untreated hypogonadism face higher incidences of . Psychological symptoms include anxiety, mood disturbances, and cognitive , often overlapping with perimenopausal experiences but occurring earlier in hypogonadal states. These may stem from estrogen's modulatory role in systems, leading to reduced emotional resilience and concentration difficulties.

Diagnosis

Clinical evaluation

The clinical evaluation of hypogonadism commences with a detailed medical history to ascertain the onset, potential etiologies, and associated factors. Clinicians assess the timing of symptom onset, distinguishing prepubertal () from postpubertal or adult-onset cases, as this informs the likelihood of congenital versus acquired causes. Family history is probed for genetic clues, such as or known syndromes like Klinefelter in males or Turner in females. Current and past medications, including glucocorticoids, opioids, or agents, are reviewed for their gonadotoxic effects, alongside chronic conditions like , , or that may contribute to secondary hypogonadism. Symptom screening refines suspicion through targeted questioning or validated tools, focusing on manifestations of gonadal insufficiency while briefly considering related signs like or mood changes. In men, the Androgen Deficiency in the Aging Male (ADAM) questionnaire, comprising 10 yes/no items on , erectile function, energy levels, and mood, serves as a simple screening aid with high sensitivity for detecting symptomatic . For women, a comprehensive menstrual history is essential, documenting patterns of primary or secondary amenorrhea, oligomenorrhea, or irregular cycles, often accompanied by queries on vasomotor symptoms, , or . The physical examination systematically evaluates secondary sexual characteristics, body composition, and organ-specific findings to corroborate historical data and differentiate primary from secondary forms. In adolescents or those with , Tanner staging quantifies breast, pubic hair, and genital development, with stages I-II suggesting hypogonadism if age-appropriate progression is absent. Adult males undergo genital assessment, including palpation for testicular presence, consistency, and size via Prader ; volumes under 4 mL bilaterally (or length <2.5 cm) strongly indicate primary testicular failure, while normal or increased size points to hypothalamic-pituitary issues. Body habitus is inspected for central adiposity, reduced muscle mass, gynecomastia, or diminished facial/body hair. In females, examination includes breast development, pubic and axillary hair distribution, clitoral size, and pelvic signs of estrogen deficiency such as atrophic vaginitis or osteoporosis risk indicators like height loss. Certain red flags during evaluation prompt urgent consideration of specific etiologies. Galactorrhea, detected via breast examination, signals potential pituitary pathology such as prolactinoma leading to secondary hypogonadism. Anosmia or hyposmia, elicited through history or simple testing like identification of common odors, raises suspicion for Kallmann syndrome, a genetic form of isolated gonadotropin-releasing hormone deficiency. When fertility preservation is a priority, evaluation adopts a multidisciplinary framework, integrating input from endocrinologists, urologists, and gynecologists to address reproductive implications early.

Laboratory testing

Laboratory testing for primarily involves blood-based hormone assays to measure sex steroid levels and gonadotropins, confirming the diagnosis when correlated with clinical symptoms. In men, the initial test is a fasting morning serum total concentration, with levels below 300 ng/dL (10.4 nmol/L) indicating potential hypogonadism; a second morning measurement is recommended for confirmation due to diurnal variation, where testosterone peaks between 7-10 AM and declines throughout the day. If total testosterone is borderline (e.g., 300-500 ng/dL), including levels around 360 ng/dL in symptomatic males, free testosterone and (SHBG) should be assessed via repeat morning testing, as treatment decisions should integrate symptoms with laboratory results rather than relying on numerical thresholds alone. In women, estradiol levels below 50 pg/mL (183 pmol/L) in the context of amenorrhea or menopausal symptoms suggest ovarian dysfunction, while follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels help differentiate primary from secondary causes. Elevated FSH and LH indicate primary hypogonadism due to gonadal failure, whereas low or inappropriately normal levels point to secondary (hypogonadotropic) hypogonadism originating from hypothalamic-pituitary dysfunction. In men with low testosterone, normal rather than suppressed gonadotropin levels reduce the likelihood of ongoing exogenous testosterone influence, as exogenous androgens typically suppress LH and FSH through negative feedback on the hypothalamic-pituitary-gonadal axis. Thresholds should be interpreted using age-adjusted reference ranges, as postmenopausal women naturally have lower estradiol (<20 pg/mL) and higher FSH (>30 IU/L), distinguishing eugonadal states from pathological hypogonadism. Additional tests include serum prolactin to evaluate for hyperprolactinemia in secondary hypogonadism, (SHBG) to calculate free testosterone or fractions, and inhibin B as a marker of Sertoli (in men) or granulosa (in women) cell function, which is typically low in primary hypogonadism. For men concerned about fertility, is essential, often revealing or in hypogonadal states. Common pitfalls in laboratory testing include assay variability, where immunoassays may overestimate or underestimate low testosterone levels compared to -based methods; thus, liquid chromatography-tandem is preferred for accuracy. can lower SHBG concentrations, reducing total testosterone while free testosterone remains normal, potentially leading to misdiagnosis of hypogonadism in obese individuals.

Imaging and differential diagnosis

Imaging plays a crucial role in evaluating the of hypogonadism, particularly to identify structural abnormalities in the hypothalamic-pituitary-gonadal axis or gonadal tissues. In cases of suspected secondary (, (MRI) of the and is recommended to detect tumors, lesions, or other pathologies such as prolactinomas or . For primary hypogonadism, in males can assess testicular size, volume, and presence of masses or , while pelvic ultrasound in females evaluates ovarian morphology and detects cysts or streaks. (DEXA) scanning is advised to measure density, as hypogonadism often leads to or , guiding risk assessment and management. Karyotyping is indicated in primary hypogonadism to identify chromosomal abnormalities, such as the 47,XXY karyotype in Klinefelter syndrome (affecting males) or 45,X in Turner syndrome (affecting females), which are common genetic causes. The European Academy of Andrology guidelines recommend karyotype analysis for men with primary hypogonadism, elevated gonadotropins, and small testes, as it confirms diagnosis in up to 90% of non-mosaic Klinefelter cases. Differential diagnosis involves distinguishing true organic hypogonadism from functional or reversible conditions. can mimic secondary hypogonadism through elevated stimulating release, leading to low gonadotropins; help exclude this. Depression and chronic stress may cause functional hypogonadism with low testosterone and gonadotropins, resolving with treatment of the underlying psychiatric condition. Hyperprolactinemia, often due to prolactinomas, suppresses and must be differentiated from idiopathic secondary hypogonadism via serum measurement; elevated levels warrant MRI to rule out pituitary adenomas. Stimulation tests further delineate pituitary and gonadal function. In males, the (hCG) stimulation test assesses response by measuring testosterone rise after hCG administration, confirming primary testicular failure if inadequate. For suspected pituitary dysfunction in secondary hypogonadism, GnRH analog stimulation evaluates gonadotropin reserve, with blunted / response indicating hypothalamic-pituitary impairment. In females, similar GnRH testing can assess for hypothalamic amenorrhea versus organic causes. According to guidelines, imaging such as pituitary MRI is warranted in secondary hypogonadism if gonadotropins are low or inappropriately normal, symptoms suggest a sellar mass, or is elevated, to exclude treatable structural lesions before confirming idiopathic . The recommends analogous evaluation in females with amenorrhea and low , emphasizing MRI for persistent hyperprolactinemia or defects.

Management and Treatment

Hormone replacement therapy

Hormone replacement therapy (HRT) for hypogonadism aims to restore physiological hormone levels, induce and maintain secondary sex characteristics, and alleviate associated symptoms such as , reduced , and bone density loss. In both males and females, the therapy targets normalization of sex steroid levels to mitigate long-term risks like and while improving quality of life, in line with 2025 guidelines from the European Association of (EAU) and International Consultation for (ICSM). For congenital cases, induction involves gradual dosing to mimic natural pubertal progression, starting with low doses and titrating upward over 2–3 years to promote genital maturation, secondary , and attainment of target . In males with hypogonadism, testosterone replacement therapy is the cornerstone, administered via intramuscular injections, transdermal gels, or subcutaneous pellets to achieve mid-normal range serum levels. Intramuscular formulations, such as or cypionate at 75–100 mg weekly, provide steady delivery, while gels (e.g., 50–100 mg daily) offer daily absorption through the skin, and pellets (e.g., 600–1200 mg every 3–6 months) ensure long-term release. Therapy requires regular monitoring of (PSA) levels to screen for prostate issues and to detect , with adjustments to maintain levels between 400–700 ng/dL; other risks include elevated red blood cell count (erythrocytosis), worsening sleep apnea, acne, and fluid retention, which are manageable with such monitoring including blood tests. Bioidentical testosterone, chemically identical to endogenous forms and derived from sources, is preferred over synthetic analogs for closer physiological , though both are effective; routes minimize hepatic first-pass effects compared to oral forms. In the 2020s, long-acting formulations like injections (every 10–12 weeks) and oral undecanoate capsules have gained prominence for improved adherence and stable in hypogonadal men. For females, particularly those with (POI), estrogen-progestin combinations are recommended to replace deficient hormones, with estrogen alone for hysterectomized women to prevent ; recent regulatory actions, including the U.S. Department of Health and Human Services (HHS) removal of misleading FDA warnings in November 2025, have reaffirmed the safety of HRT when appropriately indicated. Common regimens include oral (0.625–1.25 mg daily) combined with (2.5–5 mg daily for 12–14 days monthly), or transdermal patches (0.025–0.1 mg daily) with micronized progesterone (200 mg daily cyclically), aiming to achieve premenopausal levels of 50–100 pg/mL, consistent with 2025 Society for guidance on female hypogonadism. These forms alleviate vasomotor symptoms, support bone health, and reduce urogenital atrophy risks. Bioidentical estrogens and progestogens, such as and micronized progesterone, are favored for their structural similarity to human hormones, potentially offering a safer profile than synthetic versions like those derived from equine sources; delivery bypasses liver metabolism, reducing risk. Recent advancements include long-acting patches and emerging digital apps for personalized dosing adjustments based on symptom tracking and lab feedback, enhancing individualized management in POI. Emerging research as of 2025 explores hormone-filled microbeads in injectable hydrogels for monthly self-administration, promising steadier release and better adherence for menopausal and POI symptoms. For pubertal induction in adolescent girls, low-dose oral or (e.g., 0.25–2 mg daily, increasing gradually) is initiated around age 12, with progestin added after 1–2 years to induce withdrawal bleeds.

Treatment of underlying causes

The treatment of underlying causes in hypogonadism aims to address specific etiologies, potentially reversing or halting the progression of gonadal dysfunction rather than relying solely on lifelong supplementation. This approach is particularly relevant for secondary hypogonadism, where hypothalamic-pituitary axis disruptions can often be mitigated if identified early, per 2025 EAU and ICSM guidelines. Reversible causes, such as functional impairments from medications, , or infections, are prioritized in clinical guidelines to restore endogenous production. Surgical interventions target structural abnormalities that impair gonadal function. For pituitary adenomas causing secondary hypogonadism through or hormone excess, transsphenoidal resection is the preferred first-line treatment, often leading to normalization of pituitary function and recovery of gonadotropin secretion in select cases. In , a primary cause of hypogonadism due to undescended testes, timely orchidopexy—typically performed between 6 and 18 months of age—positions the testis in the , reducing the risk of long-term testicular damage and associated hypogonadism. Medical therapies focus on pharmacological correction of reversible endocrine disruptions. Dopamine agonists, such as or , are the cornerstone for prolactinomas, which hypersecrete and suppress the hypothalamic-pituitary-gonadal (HPG) axis; these agents shrink tumors, normalize levels, and restore testosterone production in a majority of men within the first year of treatment. For obesity-related secondary hypogonadism, where excess adiposity suppresses the HPG axis via increased activity and inflammation, lifestyle interventions emphasizing —through diet, exercise, or —can significantly elevate testosterone levels and improve gonadal function, with meta-analyses showing sustained benefits proportional to the degree of weight reduction; as of 2025, GLP-1/GIP receptor agonists like have demonstrated efficacy in raising testosterone and alleviating symptoms in obese men with metabolic hypogonadism, often comparably or superior to traditional methods. Iron chelation therapy, using agents like , is indicated for hemochromatosis, where damages the pituitary and gonads; this approach reduces hepatic and endocrine iron deposition, potentially reversing hypogonadism in early-stage disease. In cases stemming from infections or toxins, prompt intervention prevents permanent gonadal injury. Bacterial , which can lead to primary hypogonadism through testicular and , is managed with antibiotics such as fluoroquinolones or trimethoprim-sulfamethoxazole, aiming to eradicate the infection and preserve testicular tissue. Cessation of use is essential for opioid-induced secondary hypogonadism, as chronic exposure suppresses ; discontinuation often leads to partial or full recovery of the HPG axis within months, underscoring the functional and reversible nature of this etiology. Similarly, avoidance of environmental exposures—such as pesticides, , or endocrine-disrupting chemicals—can mitigate toxin-related HPG suppression, though evidence for full reversibility varies by exposure duration and intensity. For genetic forms like , which involves congenital HPG defects, treatments remain primarily supportive with hormone replacement, as gene therapy remains in preclinical stages without established clinical applications. Overall, guidelines from endocrine societies emphasize evaluating and treating reversible causes first in secondary hypogonadism, with studies indicating improvement in gonadal function for up to 50% of functional cases upon etiology removal, though outcomes depend on the underlying mechanism and intervention timing.

Fertility and reproductive options

Hypogonadism often leads to due to impaired production, but various preservation and assisted reproductive techniques can be employed, particularly for individuals with secondary (hypogonadotropic) forms where gonadal function may be inducible. In males with hypogonadism, sperm retrieval techniques such as testicular sperm extraction (TESE) are utilized for those with , allowing direct aspiration of sperm from testicular tissue for use in (ICSI) during fertilization (IVF). For , pulsatile (GnRH) therapy mimics physiological pulsatile secretion to stimulate the pituitary and induce , often requiring 3-6 months of treatment before is achieved. Additionally, (hCG) alone or combined with human menopausal gonadotropin (hMG) can be administered to promote testicular function and in these patients. For females with hypogonadism, is a key preservation strategy performed prior to gonadotoxic treatments or in cases of anticipated ovarian failure, involving ovarian stimulation followed by egg retrieval and to maintain future reproductive potential. In instances of primary ovarian failure, IVF using donor eggs offers a viable path to , where eggs from a healthy donor are fertilized with partner or donor and transferred to the recipient's . Fertility induction in both sexes with secondary hypogonadism typically involves hMG and hCG; in males, this combination induces with success rates of 75-80% in congenital hypogonadotropic cases, while in females, it supports with cumulative live birth rates reaching approximately 60% after multiple cycles. Outcomes are generally lower in primary hypogonadism due to inherent gonadal damage, with induction rates around 50% or less and reliance on donor gametes for . Patients at risk of iatrogenic hypogonadism, such as those facing , should receive comprehensive counseling on these options at to facilitate informed decisions about preservation before treatment initiation.

Complications and Prognosis

Associated health risks

Untreated hypogonadism in men, characterized by testosterone deficiency, significantly impairs health by accelerating and reducing bone mineral density (BMD), leading to an elevated risk of and . Testosterone plays a critical role in maintaining bone mass, and its deficiency results in inadequate mineralization, with studies showing increased risk approximately 1.5-2 times higher compared to eugonadal men. This heightened risk is particularly pronounced in conditions like or acquired hypogonadism. Cardiovascular complications arise from the hypogonadal state, which promotes , , and , thereby elevating the overall risk of coronary heart disease, , and . Men with hypogonadism face a 1.5- to 2-fold increased incidence of cardiovascular events compared to those with normal testosterone levels, independent of traditional risk factors. Additionally, testosterone deficiency contributes to through and visceral fat accumulation, further compounding cardiovascular vulnerability by raising the prevalence of and . Low testosterone in hypogonadism is associated with an increased risk of hypertension, often in the context of metabolic syndrome, obesity, or other cardiovascular risk factors such as smoking or family history of hypertension, although the causal relationship is complex and may be influenced by these confounders. Untreated hypogonadism in women, characterized by deficiency, significantly impairs health by accelerating and reducing bone mineral density (BMD), leading to an elevated risk of and fractures. plays a critical role in maintaining bone mass, and its deficiency results in inadequate mineralization during or accelerated loss in adulthood, with studies showing cumulative BMD reductions of approximately 9-10% over a decade in affected women, equivalent to 1-2% annual loss in early stages. This heightened fracture risk is particularly pronounced in conditions like premature ovarian insufficiency (POI), where estrogen deprivation can double the risk of compared to age-matched peers. Cardiovascular complications arise from the hypoestrogenic state, which promotes , , and , thereby elevating the overall risk of coronary heart disease, , and . Women with POI or other forms of hypogonadism face a twofold to threefold increased incidence of cardiovascular events compared to those with normal ovarian function, independent of traditional risk factors like or . Additionally, estrogen deficiency contributes to through and visceral fat accumulation, further compounding cardiovascular vulnerability by raising the prevalence of and . Regarding malignancy, untreated hypogonadism generally does not directly elevate risk due to low levels, but certain subtypes like POI have been associated with a modestly increased incidence, potentially linked to underlying genetic factors or prolonged exposure to other hormones. However, the primary oncogenic concern in hypoestrogenic states is indirect, as unaddressed in some cases may lead to irregular exposure without progesterone opposition, heightening risk over time. In men, low testosterone has been linked to increased risk in some studies, though evidence is mixed. Neurological risks include cognitive decline and sleep disturbances, with sex hormone deficiency impairing hippocampal function and , resulting in measurable deficits in global cognition and executive performance. Individuals with hypogonadism show up to a 20-30% greater likelihood of compared to eugonadal counterparts, exacerbated by genetic factors like the APOE-ε4 allele. Furthermore, low sex hormones correlate with , as those with hypogonadism exhibit higher apnea-hypopnea indices and prevalence, potentially due to altered upper airway and fat distribution.

Long-term outcomes

With appropriate (HRT), individuals with hypogonadism can achieve normalized and substantial symptom resolution, including stabilization or improvement in . In men receiving long-term testosterone replacement therapy (TRT), mortality rates are significantly lower compared to untreated cases, with one study reporting 10.3% mortality in treated groups versus 20.7% in untreated over several years of follow-up. Similarly, therapy in women with hypogonadism restores hormonal balance, mitigating risks of long-term complications and supporting overall healthspan. outcomes are particularly favorable, as TRT in hypogonadal men leads to measurable increases, with the most pronounced gains occurring in the first year of treatment. In contrast, untreated hypogonadism is associated with elevated mortality risk and irreversible consequences. Men with low testosterone levels who remain untreated exhibit nearly double the compared to those receiving , with hazard ratios indicating a 2-fold increase in risk. Severe untreated cases can shorten lifespan, as evidenced by higher all-cause mortality in observational cohorts. Primary hypogonadism often results in permanent without intervention, as gonadal damage precludes natural production. Ongoing monitoring is essential for optimizing long-term outcomes in treated patients. Guidelines recommend annual assessments of levels, , and in men on TRT, with adjustments based on mid-interval trough levels. (DEXA) scans for evaluation are advised every 1-2 years, particularly in those with baseline low mineral density, to track HRT efficacy. For individuals pursuing , regular tracking of or via and assays ensures timely interventions. Early diagnosis profoundly influences prognosis by enabling timely interventions that prevent developmental deficits. Puberty induction in adolescents with congenital hypogonadism averts issues such as short stature and psychosocial challenges, leading to improved adult height and quality of life. Delays in recognition can exacerbate bone loss and metabolic disturbances, underscoring the value of prompt screening in at-risk populations. Recent advances in therapies have expanded reproductive options, particularly for women with hypogonadism. stimulation combined with in vitro fertilization-embryo transfer (IVF-ET) yields satisfactory rates in , enabling conception even after prolonged amenorrhea. These approaches, including supplementation, can extend the effective window, supporting into later reproductive years for select patients.

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