Materiały źródłowe

• #1 Male Hypogonadism – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532933/

  Male hypogonadism, acquired or congenital, can be caused by defects that interfere with the hypothalamic-pituitary-testicular axis. […] It is essential to distinguish between primary hypogonadism and secondary hypogonadism. […] Defects that interfere with interactions in the hypothalamic-pituitary-testicular axis can cause male hypogonadism as well as primary testicular disorders. Such defects may be acquired or congenital. […] Primary hypogonadism occurs when testicular steroidogenesis is insufficient to synthesize adequate testosterone levels, a testicular disorder. Secondary hypogonadism transpires when chemical signaling to the testes (either from the pituitary, through LH, or from the hypothalamus, through GnRH) cannot stimulate sufficient Leydig cell testosterone production. […] Testosterone production by testicular Leydig cells depends on stimulation from the anterior pituitary gland, which secretes pulses of luteinizing hormone (LH) into the circulation.

• #1 EAU Guidelines on Sexual and Reproductive Health – Uroweb

  https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-hypogonadism

  Male hypogonadism can be classified according to the aetiology into primary hypogonadism or secondary hypogonadism. A compensated or subclinical form of hypogonadism, characterised by normal testosterone serum levels and elevated luteinising hormone (LH) production, has also been reported; the clinical significance of this condition is unclear. […] The classification of hypogonadism has also been divided into two broad categories: Classical/Organic and Functional, often but not correctly identified as LOH. The clinical effects of testosterone deficiency are however common to all patients independent of the cause of the hypogonadism; although, they may vary in severity or as a result of age of onset. […] Late onset hypogonadism represents an even broader clinical entity including adult onset forms which can have an organic or functional origin and can be primary or secondary. Late onset hypogonadism is frequently diagnosed in the absence of an identifiable classical cause of hypogonadism, which becomes more prevalent with age. By definition LOH must comprise both persistent specific symptoms and biochemical evidence of testosterone deficiency.

• #1 Clinical features and diagnosis of male hypogonadism – UpToDate

  https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-male-hypogonadism

  INTRODUCTION […] The clinical features of male hypogonadism are sufficiently well recognized, the causes sufficiently well known, and the tests of the hypothalamic-pituitary-testicular axis sufficiently accurate to permit the diagnosis in most patients. […] BACKGROUND […] Hypogonadism in a male refers to a decrease in one or both of the two major functions of the testes: sperm production or testosterone production. These abnormalities can result from disease of the testes (primary hypogonadism) or disease of the hypothalamus or pituitary (secondary hypogonadism). The distinction between these disorders, which will be described below, is made by measurement of the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH): […] ● The patient has primary hypogonadism if the serum testosterone concentration and/or the sperm count are below normal and the serum LH and/or FSH concentrations are above normal. […] ● The patient has secondary hypogonadism if the serum testosterone concentration and/or the sperm count are below normal and the serum LH and/or FSH concentrations are normal or low.

• #1 EAU Guidelines on Sexual and Reproductive Health – Uroweb

  https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-hypogonadism

  Finally, hypogonadism can also result from several conditions leading to reduced sensitivity/insensitivity to testosterone and its metabolites. […] The current guidelines maintain a classification of Primary and Secondary Hypogonadism, with special reference to LOH. The classification, based on the aetiology of hypogonadism, allows clinicians to adequately select appropriate treatment. In patients with secondary hypogonadism, both fertility and testosterone normalisation can be theoretically achieved with adequate treatment, whereas in primary hypogonadism only testosterone therapy can be considered, which eventually impairs fertility due to suppression of the HPT axis.

• #1 Male Hypogonadism – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism

  Hypogonadism is defined as testosterone deficiency with associated symptoms or signs, deficiency of spermatozoa production, or both. It may result from a disorder of the testes (primary hypogonadism) or of the hypothalamic-pituitary axis (secondary hypogonadism). Both may be congenital or acquired as the result of aging, disease, drugs, medications, or other factors. Additionally, a number of congenital enzyme deficiencies cause varying degrees of target organ androgen resistance. Diagnosis is confirmed by hormone levels. Treatment varies with etiology but typically includes gonadotropin-releasing hormone, gonadotropin, or testosterone replacement. […] Primary hypogonadism involves failure of the testes to respond to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). When primary hypogonadism affects testosterone production, testosterone is insufficient to inhibit production of FSH and LH; hence, FSH and LH levels are elevated.

• #1 Male Hypogonadotropic Hypogonadism: The Emerging Role of Clomiphene

  https://consultqd.clevelandclinic.org/male-hypogonadotropic-hypogonadism-the-emerging-role-of-clomiphene

  Hypogonadotropic hypogonadism, also known as secondary hypogonadism, is caused by disfunction of the pituitary gland, which leads to insufficient production of testosterone in men. […] Two types of pituitary disfunction can cause hypogonadotropic hypogonadism: one is damage to the gland itself, for example, due to a mass, inflammation or radiation therapy to the head or neck, and the other is suppression of pituitary gland hormones. […] Clomiphene is a selective estrogen receptor modulator (SERM). It works by interacting with the estrogen receptor on the pituitary gland. Clomiphene binds to this receptor and blocks the effects of estrogen on the pituitary gland. […] Clomiphene helps by blocking that estrogen feedback and reducing the off signal to the pituitary, so that it can further stimulate the testes to produce testosterone. This way, clomiphene helps interrupt the pathway that leads to hypogonadotropic hypogonadism.

• #1 Hypogonadism: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/922038-overview

  Hypogonadism refers to a condition in which little or no hormone is produced by the testes or ovaries. The condition can be hypergonadotropic (primary, resulting when the gonads fail) or hypogonadotropic. The latter can result from failure of the hypothalamic luteinizing-hormone releasing hormone [LHRH] pulse generator or from the inability of the pituitary to respond with secretion of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]. […] Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level. Hypergonadotropic hypogonadism (primary hypogonadism) results if the gonad does not produce the amount of sex steroid sufficient to suppress secretion of LH and FSH at normal levels. Hypogonadotropic hypogonadism may result from failure of the hypothalamic LHRH pulse generator or from inability of the pituitary to respond with secretion of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as one aspect of multiple pituitary hormone deficiencies resulting from malformations (eg, septooptic dysplasia, other midline defects) or lesions of the pituitary that are acquired postnatally.

• #1 Hypogonadism: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/922038-overview

  Normosmic hypogonadotropic hypogonadism, in which the sense of smell is not disrupted, has been associated with mutations in GNRH1, KISS1R, and GNRHR genes. Although their exact functions are unclear, the genes TAC3 and TACR3 have also been associated with normosmic hypogonadotropic hypogonadism. Kallmann syndrome (anosmic hypogonadotropic hypogonadism) has been associated with mutations in KAL1, FGFR1, FGF8, PROK2, and PROKR2 genes. The relationship with Kallmann syndrome is thought to be because these genes are all related to the development and migration of GnRH neurons. Mutations of an additional gene, CHD7, which has been associated with CHARGE syndrome, has also been found in patients with normosmic or anosmic hypogonadotropic hypogonadism.

• #1 Male hypogonadism – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/male-hypogonadism/symptoms-causes/syc-20354881

  A number of conditions can cause secondary hypogonadism, including: […] An abnormality in the pituitary gland can impair the release of hormones from the pituitary gland to the testicles, affecting normal testosterone production. […] Certain inflammatory diseases, such as sarcoidosis, histiocytosis and tuberculosis, involve the hypothalamus and pituitary gland and can affect testosterone production. […] The use of certain drugs, such as opiate pain medications and some hormones, can affect testosterone production. […] As men age, there’s a slow, progressive decrease in testosterone production. The rate varies greatly.

• #1 Male Hypogonadism – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism

  Secondary hypogonadism is failure of the hypothalamus to produce gonadotropin-releasing hormone (GnRH), as in idiopathic hypogonadotropic hypogonadism, or of the pituitary gland to produce enough FSH and LH. In secondary hypogonadism, testosterone levels are low and levels of FSH and LH are low or inappropriately normal. […] Increases in FSH and LH are more sensitive for primary hypogonadism than are decreases in testosterone levels. Levels of FSH and LH also help determine whether hypogonadism is primary or secondary. High gonadotropin levels, even with low-normal testosterone levels, indicate primary hypogonadism, whereas gonadotropin levels that are low or lower than expected for the level of testosterone indicate secondary hypogonadism. […] Testosterone replacement therapy can relieve symptoms of hypogonadism but does not restore fertility. Testosterone replacement therapy can relieve symptoms of hypogonadism but does not restore fertility. […] Gonadotropin replacement therapy can usually restore fertility in men with secondary hypogonadism.

• #1 Male hypogonadism: pathogenesis, diagnosis, and management – PubMed

  https://pubmed.ncbi.nlm.nih.gov/39159641/

  Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. […] However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. […] Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism.

• #1 Male hypogonadism in overweight and obesity

  https://www.oaepublish.com/articles/mtod.2023.05

  Obesity-related gonadal dysfunction in males has been defined recently as male obesity secondary hypogonadism (MOSH). […] In pathophysiological terms, excess body fat is associated with leptin and insulin resistance. […] Accelerated synthesis of leptin and hyperinsulinemia downregulate the expression of kisspeptin receptors and, consequently, the action of kisspeptin. […] In obese males, enhanced activity of the aromatase enzyme is associated with an increase in the conversion of circulating testosterone to estrogen, further promoting a state of hypogonadism. […] The temporal relationship between testosterone deficiency (TD) and obesity is complex, not well-defined, and remains, at best, poorly understood. Overall, the relationship between obesity and hypogonadism is complex and bi-directional. Excessive body fat is linked with lower testosterone production and vice versa; hypogonadal men are more prone to body fat accumulation.

• #1 Male hypogonadism in overweight and obesity

  https://www.oaepublish.com/articles/mtod.2023.05

  The GELDING (Gut Endotoxin Leading to a Decline IN Gonadal function) theory supports that a key inflammatory trigger for developing MOSH is the trans-mucosal passage of bacterial lipopolysaccharide from the lumen of the gut to the circulation. […] Testosterone plays a crucial role in regulating body composition, exerting various molecular functions. […] Testosterone has been found to inhibit the differentiation of adipocytes while enhancing the expansion of myocytes, as both cell types share a common developmental origin. […] Low testosterone levels contribute to increased adiposity by promoting adipogenesis, particularly in visceral fat depots. […] Hypogonadism has also been highlighted to represent one of the significant hormonal disorders related to future CKD risk. […] The pathophysiological link remains under investigation, yet there is evidence of a relation between intrahepatic fat accumulation and metabolic risk factors in CKD.

• #1 EAU Guidelines on Sexual and Reproductive Health – Uroweb

  https://uroweb.org/guidelines/sexual-and-reproductive-health/chapter/male-hypogonadism

  Male hypogonadism is a clinical syndrome which comprises of symptoms with or without signs and biochemical evidence of testosterone deficiency. Hypogonadism is associated with decreased testicular function and production of androgens and/or impaired sperm production. This may be caused by impaired testicular function (hypergonadotropic hypogonadism or primary hypogonadism) or as a result of inadequate stimulation of the testes by the hypothalamic-pituitary axis (hypogonadotropic hypogonadism or secondary hypogonadism) or uncommonly by reduced ability of testosterone to stimulate the androgen receptor at the cellular level. Hypogonadism can adversely affect multiple organ functions and quality of life (QoL). […] The prevalence of LOH increases with age, with the major causes being obesity, other co-morbidities (e.g., diabetes) and overall poor health. The incidence of hypogonadism has been reported to be between 12.3 and 11.7 cases per 1,000 people per year. Aging accounts for a low percentage of hypogonadism, as there is only a small gradual decline in testosterone, up to the age of 80 years, in healthy aging men. In men aged 40-79 years, the incidence of symptomatic hypogonadism varies between 2.1 and 5.7%.

• #1 Current National and International Guidelines for the Management of Male Hypogonadism: Helping Clinicians to Navigate Variation in Diagnostic Criteria and Treatment Recommendations

  https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2020.760

  However, EMAS also found the overwhelming contribution to the apparent age-related decline in T levels to reside not in chronological aging per se, but rather in the accumulation of age-associated co-morbidities, such as obesity, resulting in suppression of LH secretion. […] Hence, questions of diagnostic specificity apply to EMAS and many other studies that describe populations of older, obese men with slightly low T levels as having adult-onset HH. […] Intriguingly, men with PH have a 3 to 4-fold relative risk of having T2DM, whether related to ageing, Klinefelter syndrome, or myotonic dystrophy. […] Over the past 20 years, there has been a worldwide surge of T prescribing, mainly for age- or obesity-related decline in serum T and/or men reporting erectile dysfunction. […] Although the benefits and safety profile of using testosterone to treat well-found MH are well-established, its use in men without a verified diagnosis of hypogonadism carries significantly less reassurance.

• #1 Hypogonadism in Systemic Diseases | SpringerLink

  https://link.springer.com/10.1007/978-3-319-44441-3_28

  Serum testosterone is often lower than normal in patients with acute or chronic systemic diseases. […] The underlying mechanisms involved in the reduced testosterone secretion depend on the type of systemic disease; thus, many pathogenetic mechanisms might be involved. […] These mechanisms involve the hypothalamus and the pituitary (secondary hypogonadism), the testis (primary hypogonadism), or both. […] The resulting low-serum testosterone could be reversible or not depending on the pathogenetic mechanism. […] Furthermore, the relationships between hypogonadism and the systemic disease are complex since these two clinical conditions may interact with each other in a bidirectional interplay. […] Biochemical hypogonadism should be differentiated into overt clinical hypogonadism and functional hypogonadism, and testosterone treatment should be offered taking into account the primary systemic disease and the possible beneficial or harmful effect on it, as well as the presence of signs and symptoms of hypogonadism. […] In this chapter the main systemic illnesses associated with hypogonadism will be discussed together with their underlying pathogenetic mechanisms, clinical significance, relevance, and clinical and practical implications.

• #1 Male Hypogonadism and Liver Disease | Oncohema Key

  https://oncohemakey.com/male-hypogonadism-and-liver-disease/

  The pathogenesis of hypogonadism in liver disease is complex, differs by diagnosis, and is hypothesized to be mediated in part by toxic metabolites affecting the hypothalamic-pituitary-gonadal (HPG) axis, hyperestrogenemia, and altered protein synthesis. […] Individuals with cirrhosis may lose luteinizing hormone (LH) pulsatility, suggestive of hypothalamic dysfunction. […] Systemic disease, in general, is associated with central hypogonadism, and is hypothesized to be due to downregulation of GnRH production by elevated inflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-) resulting in functional suppression of the HPG axis. […] However, hypogonadism in the setting of liver disease may also be due to testicular damage. […] In particular, ethanol and its metabolites have been shown to exert a toxic effect on Leydig cells and are involved in onset of the fibrogenic processes.

• #1 Testosterone treatment of male hypogonadism – UpToDate

  https://www.uptodate.com/contents/testosterone-treatment-of-male-hypogonadism

  Hypogonadism in a male refers to a decrease in either of the two major functions of the testes: sperm production or testosterone production. These abnormalities can result from disease of the testes (primary hypogonadism) or disease of the pituitary or hypothalamus (secondary hypogonadism). […] Testosterone has many different biologic effects, at least in part because it can act as three hormones. It can act directly by binding to the androgen receptor. It can also act in tissues that express the enzyme 5-alpha-reductase, via conversion to dihydrotestosterone, which binds more avidly to the androgen receptor than testosterone itself. Finally, it can act as an estrogen following conversion by aromatase to estradiol, which binds to the estrogen receptor. […] Testosterone requires conversion to dihydrotestosterone for its action on the external genitalia (which include the prostate gland) and sexual hair. This mechanism provides the basis for the use of the 5-alpha-reductase inhibitor, finasteride, to treat benign enlargement of the prostate and male pattern baldness.

• #1 Male Hypogonadism – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532933/

  Low testosterone is a known risk factor for cardiovascular disease. […] Testosterone has 3 main hormonal effects. […] Testosterone therapy in proven hypogonadal men has been shown in clinical trials to produce statistically significant improvements in libido, anemia, bone mineral density, lean body mass, depression, and erectile function. […] Testosterone supplementation will decrease sperm count and fertility unless FSH levels are maintained with clomiphene citrate or hCG therapy. […] The goal of therapy is to avoid exceeding the normal maximum testosterone blood level (which peaks 2 days after a testosterone injection) while maintaining normal serum androgen levels and adequately treating the instigating symptom, which may take up to 6 months. […] Testosterone levels should be measured every 6 to 12 months while on therapy. […] Testosterone is converted to estrogen through aromatization, causing hyperestrogenism. If this occurs, aromatase inhibitors may be necessary.

• #1 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. […] There is a bidirectional relationship between obesity and hypogonadism. In population-based studies, obesity is the single most important factor resulting in testosterone deficiency. Similarly, testosterone deficiency can cause increased adipogenesis and visceral obesity as evidenced by rapid weight gain observed in men following androgen deprivation therapy or surgical castration.

• #1 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  Testosterone exerts an anti-inflammatory effect as it prevents adipocyte hypertrophy and dysfunction. Testosterone and its aromatisation product, oestradiol, activate androgen receptors (AR) and estrogen receptors (ER and ER) within the visceral adipose tissue, with a resultant decrease in the release of adipokines (leptin, tumor necrosis factor alpha [TNF-], interleukin-6 [IL-6], osteoprotegerin, monocyte chemoattractant protein-1) and increase in the release of adiponectin and visfatin. […] During testosterone deficiency, which is a proinflammatory state, the increased fat mass leads to adipocyte dysfunction, resulting in a decrease in adiponectin and an increase in adipokines such as leptin, IL-1, IL-6, and TNF- secreted from both adipocytes and activated macrophages. […] These adipokines further worsen the inflammation and induce a state of systemic insulin resistance.

• #1 Male hypogonadism in overweight and obesity

  https://www.oaepublish.com/articles/mtod.2023.05

  The relation between hypogonadism and obstructive sleep is bi-directional. […] The efficacy of weight loss management in controlling obesity-related hypogonadism largely depends on the extent of weight loss. […] Testosterone replacement has been proven to be beneficial in the treatment of hypogonadal patients.

• #1 Effect of exogenous glucocorticoids on male hypogonadism

  https://www.spandidos-publications.com/10.3892/br.2020.1319

  The aim of the present study was to investigate the effects of exogenous glucocorticoids (GCs), a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal axis, and to determine their secondary effects in male patients. […] Current GC exposure significantly decreased the total and free testosterone levels, whereas previous GC exposure increased estradiol (E2) levels, with the 31 patients on oral dexamethasone (cumulative dose, 18.9 mg) exhibiting a 7.5-fold increased risk of being diagnosed with hypogonadism. […] Exogenous GC causes an acute reduction in T levels in men by directly suppressing gonadal steroid secretion; thus, GC therapy frequently and significantly decreases the serum T levels. Furthermore, this effect appears to be mediated by the suppression of GnRH secretion by the hypothalamus.

• #1 :: WJMH :: World Journal of Men’s Health

  https://wjmh.org/DOIx.php?id=10.5534/wjmh.190002

  Male hypogonadism is a clinical entity characterized by low serum testosterone levels in conjunction with systemic symptoms that include fatigue, erectile dysfunction and mood changes. […] Any dysregulation of this pathway can lead to male hypogonadism, infertility, or a combination thereof. […] Exogenous testosterone’s deleterious effects on male reproduction stem from its disruption of the above described male HPG axis and the resulting decreases in both serum FSH and LH. […] Consequently, exogenous testosterone almost universally leads to low intra-testicular testosterone with resulting atrophy of the germinal epithelium and subsequent azoospermia in upwards of 40% of men. […] Multiple studies have documented long-term hypogonadism stemming from prior AAS use. […] The threat that AAS use poses to future fertility and proper Sertoli and Leydig cell function cannot be overstated.

• #1 Clomiphene Citrate Treatment as an Alternative Therapeutic Approach for Male Hypogonadism: Mechanisms and Clinical Implications

  https://www.mdpi.com/1424-8247/17/9/1233

  Studies have demonstrated that clomiphene could cause significant increases in testosterone, LH, and FSH levels and testosterone/estradiol ratios, thereby positively influencing sperm concentration and motility. […] Clomiphene treatment has its limitations. Unlike TRT, clomiphene targets the HPG axis, necessitating a functional HPG axis for its anti-estrogenic effects to be effective. […] Clomiphene is considered a cost-effective medication compared with TRT; however, extensive direct comparison research related to male hypogonadism is still lacking.

• #1 Hypogonadism – Wikipedia

  https://en.wikipedia.org/wiki/Hypogonadism

  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. […] Male primary or hypergonadotropic hypogonadism is often treated with testosterone replacement therapy if they are not trying to conceive. […] Another treatment for hypogonadism is human chorionic gonadotropin (hCG). This stimulates the LH receptor, thereby promoting testosterone synthesis. […] 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.

• #1 Male Central Hypogonadism in Paediatrics – the Relevance of Follicle-stimulating Hormone and Sertoli Cell Markers | [current-page:pager]touchENDOCRINOLOGY

  https://touchendocrinology.com/pediatric-endocrinology/journal-articles/male-central-hypogonadism-in-paediatrics-the-relevance-of-follicle-stimulating-hormone-and-sertoli-cell-markers/

  The limited number of studies available to date demonstrate that a sequential treatment approach with rhFSH priming to induce Sertoli cell proliferation, before adding hCG or rhLH to provoke an increase in intratesticular testosterone concentration and Sertoli cell maturation, shows encouraging results in terms of induction of testicular growth and sperm production.

• #1 Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

  https://www.wjgnet.com/2220-6124/full/v4/i2/245.htm

  The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. […] Our results demonstrated that exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. […] Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. […] At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. […] We concluded that exogenous testosterone supplementation decreases sperm production. […] It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility.

• #1 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  In men with suspected MOSH, lifestyle modification, including weight reduction, optimal treatment of diabetes and other comorbidities, should comprise first-line treatment of the condition. If these measures fail to normalise the androgen deficiency symptoms and/or low testosterone levels, despite successful weight loss, clinicians should repeat evaluations to rule out organic HPT axis suppression.

• #2 Pathogenesis, evaluation and treatment of hypogonadism in men | Health & Environmental Research Online (HERO) | US EPA

  https://hero.epa.gov/hero/index.cfm/reference/details/reference_id/2736855

  Hypogonadism in men is defined as a complex of signs and symptoms due to testosterone deficiency or inappropriate production, which occurs in about 1-2%. […] Classically hipogonadism is divided into primary (hypergonadotropic) and secondary (hypogonadotropic). […] The most common causes of primary hypogonadism is Klinefelter’s syndrome, while secondary–pituitary tumors. […] „Peripheral” hypogonadism results from androgen receptor polymorphism. […] The role of therapy of hypogonadism is to restore or maintain proper spermatogenesis as well as testosterone replacement therapy. […] Gonadotropin and testosterone therapy is available in treatment of hypogonadism in men. […] The treatment strategy depends on the age of patient and the goals of therapy (restore of fertility and/or produce and maintain of virilization). […] The gonadototropins and GnRH are useful in spermetogenesis stimulation. […] The testosterone replacement therapy is efficacious and safe.

• #2 Male Hypogonadism – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism

  Hypogonadism is defined as testosterone deficiency with associated symptoms or signs, deficiency of spermatozoa production, or both. It may result from a disorder of the testes (primary hypogonadism) or of the hypothalamic-pituitary axis (secondary hypogonadism). Both may be congenital or acquired as the result of aging, disease, drugs, medications, or other factors. Additionally, a number of congenital enzyme deficiencies cause varying degrees of target organ androgen resistance. Diagnosis is confirmed by hormone levels. Treatment varies with etiology but typically includes gonadotropin-releasing hormone, gonadotropin, or testosterone replacement. […] Primary hypogonadism involves failure of the testes to respond to follicle-stimulating hormone (FSH) and luteinizing hormone (LH). When primary hypogonadism affects testosterone production, testosterone is insufficient to inhibit production of FSH and LH; hence, FSH and LH levels are elevated.

• #2 Male Hypogonadism | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23268

  Primary hypogonadism (testicular failure) is diagnosed by persistently low testosterone measurements with above-normal LH levels. […] Secondary hypogonadism (pituitary failure) is characterized by low serum testosterone with normal or low LH levels. Causes of secondary hypogonadism include Kallman syndrome, pituitary disorders, HIV, obesity, surgery, trauma, and stress-induced hypogonadism. […] Primary hypogonadism occurs when testicular steroidogenesis is insufficient to synthesize adequate testosterone levels, a testicular disorder. Secondary hypogonadism transpires when chemical signaling to the testes (either from the pituitary, through LH, or from the hypothalamus, through GnRH) cannot stimulate sufficient Leydig cell testosterone production. Low testosterone is a known risk factor for cardiovascular disease.

• #2 Male hypogonadism – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/male-hypogonadism/symptoms-causes/syc-20354881

  Male hypogonadism is a condition in which the body doesn’t produce enough of the hormone that plays a key role in masculine growth and development during puberty (testosterone) or enough sperm or both. […] Male hypogonadism means the testicles don’t produce enough of the male sex hormone testosterone. There are two basic types of hypogonadism: […] This type of hypogonadism indicates a problem in the hypothalamus or the pituitary gland parts of the brain that signal the testicles to produce testosterone. […] Either type of hypogonadism can be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection. […] In secondary hypogonadism, the testicles are normal but don’t function properly due to a problem with the pituitary or hypothalamus.

• #2 :: WJMH :: World Journal of Men’s Health

  https://wjmh.org/DOIx.php?id=10.5534/wjmh.190061

  A dichotomic distinction between organic and functional hypogonadism is emerging. The former is an irreversible condition due to congenital or acquired organic damage of the brain centers or of the testis. Conversely, the latter is a potentially reversible form, characterized by borderline low testosterone (T) levels mainly secondary to age-related comorbidities and metabolic derangements, including metabolic syndrome (MetS). […] In particular, the latter metabolic conditions increase the risk of secondary HG, whereas the aging process per se increases the likelihood of having a primary HG. […] A clear distinction between an organic and a functional HG was formalized few years ago in a perspective article by Grossmann and Matsumoto. Organic HG is an essentially irreversible HG, characterized by specific symptoms and signs and very low T levels. In organic HG, TTh is supposed to result in expected net effects, along with a reasonable therapy risk, when considering benefits. In contrast, functional HG is a reversible form, with borderline low T levels, characterized by sexual symptoms that are only partially ameliorated by TTh, and, more importantly, with an unknown therapy risk.

• #2 Male late-onset hypogonadism: pathogenesis, diagnosis and treatment | Nature Reviews Urology

  https://www.nature.com/articles/nrurol.2011.47

  Some aging men develop a condition of suppressed serum testosterone levels, which is associated with diffuse sexual, physical and psychological symptoms. […] The diagnosis of LOH is often uncertain because symptoms (occurring in 20-40% of men) and low circulating testosterone (found in 20% of men 70 years of age) seldom occur together. […] The strict diagnostic criteria for LOH include reproducibly low serum testosterone levels and sexual symptoms, including erectile dysfunction and reduced frequency of sexual thoughts and morning erections. […] Using these diagnostic criteria, only 2% of 40-80-year-old men have LOH. […] Obesity and impaired general health (including diabetes mellitus, cardiovascular and chronic obstructive pulmonary disease, and frailty) are more common reasons for low testosterone than advanced age per se.

• #2 Male Hypogonadism – Genitourinary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/genitourinary-disorders/male-reproductive-endocrinology-and-related-disorders/male-hypogonadism

  Secondary hypogonadism is failure of the hypothalamus to produce gonadotropin-releasing hormone (GnRH), as in idiopathic hypogonadotropic hypogonadism, or of the pituitary gland to produce enough FSH and LH. In secondary hypogonadism, testosterone levels are low and levels of FSH and LH are low or inappropriately normal. […] Increases in FSH and LH are more sensitive for primary hypogonadism than are decreases in testosterone levels. Levels of FSH and LH also help determine whether hypogonadism is primary or secondary. High gonadotropin levels, even with low-normal testosterone levels, indicate primary hypogonadism, whereas gonadotropin levels that are low or lower than expected for the level of testosterone indicate secondary hypogonadism. […] Testosterone replacement therapy can relieve symptoms of hypogonadism but does not restore fertility. Testosterone replacement therapy can relieve symptoms of hypogonadism but does not restore fertility. […] Gonadotropin replacement therapy can usually restore fertility in men with secondary hypogonadism.

• #2 Hypogonadism: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/922038-overview

  Hypogonadism refers to a condition in which little or no hormone is produced by the testes or ovaries. The condition can be hypergonadotropic (primary, resulting when the gonads fail) or hypogonadotropic. The latter can result from failure of the hypothalamic luteinizing-hormone releasing hormone [LHRH] pulse generator or from the inability of the pituitary to respond with secretion of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]. […] Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level. Hypergonadotropic hypogonadism (primary hypogonadism) results if the gonad does not produce the amount of sex steroid sufficient to suppress secretion of LH and FSH at normal levels. Hypogonadotropic hypogonadism may result from failure of the hypothalamic LHRH pulse generator or from inability of the pituitary to respond with secretion of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as one aspect of multiple pituitary hormone deficiencies resulting from malformations (eg, septooptic dysplasia, other midline defects) or lesions of the pituitary that are acquired postnatally.

• #2 Hypogonadism pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hypogonadism_pathophysiology

  Hypogonadism pathophysiology depends mainly on the deficiency of the testosterone hormone. Testosterone is secreted in response to stimulation from the brain to the hypothalamus which secretes the gonadotropin releasing hormones (GnRH). GnRH deficiency may lead to decrease of testosterone levels and eventually causing hypogonadism. Genetic mutations have a major role in the development of hypogonadism as well as other factors. There are more than 25 gene mutations participate in the pathogenesis of hypogonadism. […] The hypogonadism pathogenesis in males depends mainly on the testosterone deficiency. Testosterone secretion occurs as the following: Testosterone is secreted in response to stimulation from the cerebral cortex to the hypothalamus. The hypothalamus by its role secrets the gonadotropin releasing hormones (GnRH). GnRH stimulates the pituitary gland which by its role secretes the gonadotropin hormones the Follicle Stimulating Hormone (FSH) and the Luteinizing Hormone (LH). In males, LH stimulates the Leydig cells in the testes which produce testosterone by converting the cholesterol to testosterone. Production of testosterone from the testes gives negative feed back to the pituitary. This feedback inhibits the production of FSH and LH from the pituitary.

• #2 Genetics of hypogonadotropic hypogonadism – Millar – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/42205/html

  Male congenital hypogonadotropic hypogonadism (CHH) is a heterogenous group of genetic disorders that cause impairment in the production or action of gonadotropin releasing hormone (GnRH). These defects result in dysfunction of the hypothalamic-pituitary-gonadal hormone axis, leading to low testosterone levels and impaired fertility. […] Genetic testing techniques have expanded our knowledge of the underlying mechanisms contributing to CHH including over 30 genes to date implicated in the development of CHH. […] It has been proposed by Young et al. that defects that occur during the development and migration of GnRH secreting neurons can ultimately lead to CHH via four broadly defined mechanisms: Defects in GnRH fate specification, Defects in GnRH neuron migration/olfactory neuron guidance, Abnormal neuroendocrine secretion/homeostasis, Gonadotrope defects. […] GnRH neuronal development is a complex process, with potential for defects at several stages of its course.

• #2 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. […] There is a bidirectional relationship between obesity and hypogonadism. In population-based studies, obesity is the single most important factor resulting in testosterone deficiency. Similarly, testosterone deficiency can cause increased adipogenesis and visceral obesity as evidenced by rapid weight gain observed in men following androgen deprivation therapy or surgical castration.

• #2

  https://journals.lww.com/aidsonline/fulltext/2022/07010/hypogonadism__a_neglected_comorbidity_in_young_and.2.aspx

  Male hypogonadism is poorly characterized in young-to-middle-aged people with HIV (PWH). […] Male hypogonadism is also correlated with aging and a number of comorbid conditions (chronic hepatitis C virus infection, use of psychotropic and intravenous drugs). […] It is mostly caused by impairment of the hypothalamic-pituitary axis (HPA). […] Recent studies have estimated its prevalence at 9.3-70% in PWH. […] Total testosterone levels are affected by changes in sex-hormone-binding globulin (SHBG) levels in PWH, in whom free testosterone assays are recommended for the diagnosis of male hypogonadism. […] Male hypogonadism remains common in young-to-middle-aged PWH with stably suppressed viral replication. […] In multivariable analysis, the risk factors predictive of male hypogonadism were age more than 43 years, total fat percentage more than 19%, and treatment including efavirenz.

• #2 Male Hypogonadism and Liver Disease | Oncohema Key

  https://oncohemakey.com/male-hypogonadism-and-liver-disease/

  Despite damage to Leydig cells, testosterone levels in patients may be normal early in the disease process due to a compensatory increase in LH. […] Estrogen levels can be elevated in men with cirrhosis, which is hypothesized to be due, at least in part, to reduced metabolism and clearance of estrogen, as well as portosystemic shunting further resulting in impaired/bypassed estradiol metabolism, and increased peripheral aromatization of testosterone. […] The liver regulates testosterone bioavailability via production of SHBG and albumin and is also responsible for the production of enzymes important in the aromatization, conversion to dihydrotestosterone (DHT) and breakdown of androgens. […] SHBG levels are frequently elevated in certain forms liver disease, resulting in increased total testosterone, but lower free or bioavailable testosterone levels.

• #2 Testosterone treatment of male hypogonadism – UpToDate

  https://www.uptodate.com/contents/testosterone-treatment-of-male-hypogonadism

  Testosterone requires conversion to estradiol for much of its action on bone. This effect is illustrated by the rare condition of aromatase deficiency in men, which results in failure of epiphyseal closure and severe osteoporosis. Treatment with estradiol corrects both. […] Testosterone also appears to require conversion to estradiol to stimulate normal sexual function and decrease body fat in men, as shown by an experiment in which men 20 to 50 years old were treated with a gonadotropin-releasing hormone (GnRH) agonist to suppress testosterone and estradiol secretion and then replaced with testosterone, with or without an aromatase inhibitor. Addition of the aromatase inhibitor partially blocked testosterone from increasing libido and erectile function and from decreasing subcutaneous and intraabdominal fat.

• #2 Current National and International Guidelines for the Management of Male Hypogonadism: Helping Clinicians to Navigate Variation in Diagnostic Criteria and Treatment Recommendations

  https://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2020.760

  Male hypogonadism (MH) termed testosterone (T) deficiency syndrome by some investigators is a clinical syndrome characterized by impaired testicular function, with reduced or absent spermatogenesis and T secretion. […] The prevalence of MH has been estimated at 6% to 12%, depending on the study population and the degree of diagnostic rigor. […] If untreated, MH can lead to sexual dysfunction, anemia, osteoporosis and fracture, myopathy and frailty, tender gynecomastia, psychosocial impairments and reduced quality of life. […] There is also a strong association of MH with obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM), although the direction of causation is unclear. […] The European Male Ageing Study (EMAS) observed serum T 8 nmol/L (230.5 ng/dL) to be associated with increased all-cause and cardiovascular (CV) mortality.

• #2 Hypogonadism in Systemic Diseases | SpringerLink

  https://link.springer.com/10.1007/978-3-319-44441-3_28

  Serum testosterone is often lower than normal in patients with acute or chronic systemic diseases. […] The underlying mechanisms involved in the reduced testosterone secretion depend on the type of systemic disease; thus, many pathogenetic mechanisms might be involved. […] These mechanisms involve the hypothalamus and the pituitary (secondary hypogonadism), the testis (primary hypogonadism), or both. […] The resulting low-serum testosterone could be reversible or not depending on the pathogenetic mechanism. […] Furthermore, the relationships between hypogonadism and the systemic disease are complex since these two clinical conditions may interact with each other in a bidirectional interplay. […] Biochemical hypogonadism should be differentiated into overt clinical hypogonadism and functional hypogonadism, and testosterone treatment should be offered taking into account the primary systemic disease and the possible beneficial or harmful effect on it, as well as the presence of signs and symptoms of hypogonadism. […] In this chapter the main systemic illnesses associated with hypogonadism will be discussed together with their underlying pathogenetic mechanisms, clinical significance, relevance, and clinical and practical implications.

• #2 Male hypogonadism in overweight and obesity

  https://www.oaepublish.com/articles/mtod.2023.05

  Obesity-related gonadal dysfunction in males has been defined recently as male obesity secondary hypogonadism (MOSH). […] In pathophysiological terms, excess body fat is associated with leptin and insulin resistance. […] Accelerated synthesis of leptin and hyperinsulinemia downregulate the expression of kisspeptin receptors and, consequently, the action of kisspeptin. […] In obese males, enhanced activity of the aromatase enzyme is associated with an increase in the conversion of circulating testosterone to estrogen, further promoting a state of hypogonadism. […] The temporal relationship between testosterone deficiency (TD) and obesity is complex, not well-defined, and remains, at best, poorly understood. Overall, the relationship between obesity and hypogonadism is complex and bi-directional. Excessive body fat is linked with lower testosterone production and vice versa; hypogonadal men are more prone to body fat accumulation.

• #2 Effect of exogenous glucocorticoids on male hypogonadism

  https://www.spandidos-publications.com/10.3892/br.2020.1319

  The decrease in the total T (TT) and free T (FT) levels in men who use GCs may be attributed to GC binding to GC receptors located in several tissues and organs in the body, such as the Leydig cells, decreasing T biosynthesis via 11-HSD1 reductase activity. Leydig cell apoptosis is another mechanism attributed to decreased T levels. […] The aim of the present study was to investigate the effects of exogenous GC use, considered a potent cause of male hypogonadism, on the function of the hypothalamic-pituitary-gonadal (HPG) axis, and to determine any secondary effects in male patients. […] In the present study, in patients currently using GC, hypogonadism manifested as low TT levels in 50% of the study sample. […] There was a 4-fold increased risk of hypogonadism (low TT levels) in patients currently using GC compared with GC-naive patients. […] Oral dexamethasone caused hypogonadism at a lower total cumulative dose.

• #2 Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

  https://www.wjgnet.com/2220-6124/full/v4/i2/245.htm

  Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment. […] Exogenous testosterone is detrimental for spermatogenesis: Exogenous testosterone’s mechanism creates a negative feedback on the hypothalamic-pituitary axis. […] These impairments on hormones result in overall decreases in intratesticular testosterone levels (ITT) as well as testosterone production. […] Exogenous testosterone treatment can suppress ITT production to such an extent that spermatogenesis can be dramatically compromised at ITT concentrations to less than 20 ng/mL. […] ITT is an absolute requirement for normal spermatogenesis. […] However, the rates of success in recovering spermatogenesis after use of exogenous T are generally quite favorable.

• #2 Hypogonadism and Health Implications in Men and Women

  https://www.verywellhealth.com/hypogonadism-8784748

  Male hypogonadism is characterized by low testosterone, also known as „low T.” […] In adult males, hypogonadism is associated with a cascade of physical, sexual, and psychological symptoms, including: […] Testosterone replacement therapy (TRT) treats male hypogonadism. […] In male hypogonadism, TRT can: […] However, most studies have not shown significant mood or energy level changes in hypogonadal men on TRT. […] Adolescent boys may be prescribed TRT to initiate puberty, achieve their target height, body composition, and bone mass, and enhance sexual function during and after puberty. […] TRT can cause side effects, especially with long-term use. […] TRT can also make an enlarged prostate worse, stimulate the growth of existing prostate cancer, and lead to polycythemia, where too many red blood cells are produced.

• #2 Hypogonadism: Pathogenesis, Diagnosis, and Treatment

  https://flore.unifi.it/handle/2158/1307670

  Male hypogonadism is a clinical syndrome arising from the failure of the testes to produce sufficient testosterone to maintain secondary sexual, reproductive and other androgen-dependent physiological functions. […] The complex genetic architecture of GnRH neuronal development and action underlying congenital isolated hypogonadotropic hypogonadism (IHH) is being gradually unraveled with up to 50% of cases now having identifiable monogenic or oligogenic mutations. […] The diagnosis of hypogonadism should be made only in men with symptoms and signs consistent with androgen deficiency abetted by consistently and unequivocally low serum testosterone concentrations in fasting morning blood, measured by an accurate and reliable method. […] Testosterone replacement therapy for confirmed organic hypogonadism is well-established and highly efficacious; a new generation of testosterone preparations have largely replaced legacy products from the 1950s.

• #2 Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

  https://www.wjgnet.com/2220-6124/full/v4/i2/245.htm

  The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. […] Our results demonstrated that exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. […] Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. […] At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. […] We concluded that exogenous testosterone supplementation decreases sperm production. […] It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility.

• #2 Clomiphene Citrate Treatment as an Alternative Therapeutic Approach for Male Hypogonadism: Mechanisms and Clinical Implications

  https://www.mdpi.com/1424-8247/17/9/1233

  Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. […] Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn, improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. […] Clomiphene competitively inhibits 17β-estradiol and blocks estrogen receptors in the hypothalamic arcuate nucleus. This action disrupts the negative feedback of estrogen at the hypothalamus and pituitary gland and stimulates the production of gonadotropin, resulting in endogenous testosterone secretion.

• #2 Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

  https://www.wjgnet.com/2220-6124/full/v4/i2/245.htm

  Testosterone therapy does not improve spermatogenesis and should not be used by men of reproductive age: This practice is not unusual. […] Testosterone therapy results in a mechanism that impairs spermatogenesis. […] Clomiphene citrate may improve serum testosterone levels: Clomiphene citrate (CC) can be a fairly effective treatment option in increasing serum testosterone levels. […] Clomiphene citrate is an effective and less expensive treatment option: Taylor et al conducted a study in which CC gave rise to significant increases in testosterone levels from baseline values. […] Long-term use of Clomiphene citrate is a safe way to improve serum testosterone levels: A similar study on clomiphene was performed by Moskovic et al where forty-six hypogonadal males with an average age of 44 years were treated with clomiphene citrate for more than 12 mo.

• #2 Hypogonadism and Health Implications in Men and Women

  https://www.verywellhealth.com/hypogonadism-8784748

  Other prescription drugs are used on their own or in combination with hormone replacement therapy in people with hypogonadism, including: […] Human chorionic gonadotropin (HCG): Delivered by injection, HCG stimulates cells in the testicles, called Leydig cells, that produce testosterone. […] Hypogonadism occurs when the ovaries or testes produce little or no sex hormones, leading to low testosterone in males and low estrogen in females. […] Primary hypogonadism occurs when the testes or ovaries do not function properly, and secondary hypogonadism occurs when the hypothalamus or pituitary gland does not work properly.

• #2 Functional hypogonadism in adolescence: an overlooked cause of secondary hypogonadism in: Endocrine Connections Volume 12 Issue 11 (2023)

  https://ec.bioscientifica.com/view/journals/ec/12/11/EC-23-0190.xml

  Recent guidelines from European Academy of Andrology (EAA) recommend lifestyle changes, including physical exercise and weight reduction, as the first line of management in overweight and obese men with functional hypogonadism since weight loss may increase testosterone concentrations. […] Energy deficiency may be a cause of (transient) hypogonadotropic hypogonadism, mimicking the initial work done on the female athlete triad. […] Outside the context of very poor general health status, chronic illness may affect the hypothalamicpituitary level or the gonads or both. […] Hypogonadism with iron overload due to transfusions is one of the most common endocrine dysfunctions and is mainly due to iron deposition within the gonads and/or the pituitary. […] Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder with a prevalence of 4.78 per 100,000 males, caused by mutations of the DMD gene, which is expressed in muscle sarcolemma and encodes the muscle protein, dystrophin.

• #2 Male hypogonadism: pathogenesis, diagnosis, and management – Excel Male TRT ForumNoteThread starterStart dateTagsmale-hypogonadism-pathogenesis-diagnosis-and-management.pdf

  https://www.excelmale.com/threads/male-hypogonadism-pathogenesis-diagnosis-and-management.30929/post-286689

  Organic male hypogonadism due to irreversible hypothalamic–pituitary–testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. […] However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. […] This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition. […] Male hypogonadism encompasses a diverse group of congenital and acquired conditions either due to intrinsic pathology in the HPT axis or reversible suppression. […] The increasing number of men presenting with functional hypogonadism poses diagnostic challenges due to subtle clinical features and controversies in diagnostic serum testosterone cut-offs. […] Similarly, treating the underlying risk factors such as obesity supersedes testosterone use, though the evidence suggests medium-term cardiovascular safety and modest symptomatic benefits of testosterone treatment in this group of men.

• #3 Hypogonadism: Pathogenesis, Diagnosis, and Treatment

  https://flore.unifi.it/handle/2158/1307670

  Male hypogonadism is a clinical syndrome arising from the failure of the testes to produce sufficient testosterone to maintain secondary sexual, reproductive and other androgen-dependent physiological functions. […] The complex genetic architecture of GnRH neuronal development and action underlying congenital isolated hypogonadotropic hypogonadism (IHH) is being gradually unraveled with up to 50% of cases now having identifiable monogenic or oligogenic mutations. […] The diagnosis of hypogonadism should be made only in men with symptoms and signs consistent with androgen deficiency abetted by consistently and unequivocally low serum testosterone concentrations in fasting morning blood, measured by an accurate and reliable method. […] Testosterone replacement therapy for confirmed organic hypogonadism is well-established and highly efficacious; a new generation of testosterone preparations have largely replaced legacy products from the 1950s.

• #3 Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/122824-overview

  Deficient hypothalamic GnRH secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation. […] Some of the genes involved in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified. However, the genes involved remain unidentified in over 50% of patients. […] Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. […] Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked idiopathic hypogonadotropic hypogonadism associated with adrenal hypoplasia congenita (AHC).

• #3 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. […] There is a bidirectional relationship between obesity and hypogonadism. In population-based studies, obesity is the single most important factor resulting in testosterone deficiency. Similarly, testosterone deficiency can cause increased adipogenesis and visceral obesity as evidenced by rapid weight gain observed in men following androgen deprivation therapy or surgical castration.

• #3 Male Obesity-related Secondary Hypogonadism – Pathophysiology, Clinical Implications and Management – touchENDOCRINOLOGY

  https://touchendocrinology.com/obesity/journal-articles/male-obesity-related-secondary-hypogonadism-pathophysiology-clinical-implications-and-management/

  Pathophysiological mechanisms for hypogonadism in obesity and for obesity in testosterone deficiency are complex and multifactorial. Individuals with MOSH exhibited a normal luteinising hormone (LH) and follicle stimulating hormone (FSH) response to gonadotropin releasing hormone (GnRH) indicating a hypothalamic defect rather than a pituitary defect. […] The hypogonadalobesityadipocytokine hypothesis is an extension of Cohens theory, which explains why the body cannot produce compensatory testosterone via increased gonadotrophin secretion and subsequent stimulation of the Leydig cells. In obese individuals, enhanced aromatase enzymes produced by adipose tissue reduce the testosterone and increase the oestrogen hormones. […] Testosterone deficiency facilitates further adipocyte differentiation, adipocyte inflammation and insulin resistance. The resultant increase in oestrogen, leptin, insulin and inflammatory cytokines result in hypothalamopituitarytesticular (HPT) axis suppression.

• #3 Low Testosterone (Low T): Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/15603-low-testosterone-male-hypogonadism

  Conditions that affect how your hypothalamus and/or pituitary gland cause secondary hypogonadism. This is known as hypogonadotropic hypogonadism because there are low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). […] Late-onset hypogonadism (LOH) is a type of secondary male hypogonadism that results from normal aging. […] As males age they have a deterioration of hypothalamic-pituitary function and Leydig cell function that decrease testosterone and/or sperm production.

• #3

  https://journals.lww.com/aidsonline/fulltext/2022/07010/hypogonadism__a_neglected_comorbidity_in_young_and.2.aspx

  Male hypogonadism was exclusively of secondary origin, as indicated by the normal or low levels of LH. […] Our data are consistent with published studies identifying hypothalamic-pituitary axis impairment as the exclusive cause of male hypogonadism. […] One of the first reasons for this is the occurrence of significant immune disorders (inappropriate secretion of cytokines). […] Several studies have also demonstrated a direct cytopathic effect of the virus, which may cause gonadal dysfunction. […] Despite the widespread use of cART, CD4+ T-cell counts remain associated with male hypogonadism. […] The early onset of male hypogonadism may reflect the premature aging of PWH. […] The correlation between age and male hypogonadism is well established, but our findings show for the first time that this correlation is independent of viral control and of total body fat percentage. […] Male hypogonadism was also associated with total body fat content, as reported for obese patients with or without HIV infection. […] Determining the factors associated with male hypogonadism could help identify patients at risk and discuss the indication for testosterone supplementation.

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