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Male Hypogonadism PowerPoint Presentation

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Description : Check out this medical titled "Male hypogonadism" by S. Hopkins, RN, BSN, EMT-P.

This medical talks about male hypogonadism, a condition in which the body doesnt produce enough testosterone, the male hormone responsible for the development of male sex organs and secondary sex characteristics, such as muscle mass, facial hair, and a deep voice.

There are two main types of male hypogonadism: primary hypogonadism and secondary hypogonadism. Primary hypogonadism occurs when there is a problem with the testes themselves, such as a genetic disorder, injury, or infection. Secondary hypogonadism occurs when there is a problem with the hypothalamus or pituitary gland, which regulate the production of testosterone.

Symptoms of male hypogonadism may include decreased sex drive, erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone density, and mood changes, such as depression or irritability.

Treatment for male hypogonadism usually involves testosterone replacement therapy, which can be administered through injections, skin patches, or gels. In some cases, treatment may also involve addressing underlying health conditions, such as diabetes or obesity, that may be contributing to the hypogonadism.

Tags : male hypogonadism, testosterone, male sex organs, secondary sex characteristics, primary hypogonadism, secondary hypogonadism

Published on : Apr 21, 2023 | Views : 2137 | Downloads : 7

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Module 2 Male hypogonadism Approval Number: G.MKT.GM.MH.04.2018.0513
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Definition Module 2: Male hypogonadism
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Several international societies have proposed definitions of hypogonadism EAU, European Association of Urology 1. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/2. Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59.
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Several international societies have proposed definitions of hypogonadism (2) ISSAM, International Society for the Study of the Aging Male Lunenfeld B et al. Aging Male. 2015;18(1):5–15.
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Several international societies have proposed definitions of hypogonadism (3) ICSM, International Consultation for Sexual Medicine; SHBG, sex hormone-binding globulin; TD, testosterone deficiency Khera M et al. J Sex Med. 2016;13(12):1787–804.
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Several international societies have proposed definitions of hypogonadism (4) ISSM, International Society for Sexual Medicine; TD, testosterone deficiency Dean JD et al. J Sex Med. 2015;12(8):1660–86.
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Classification and etiology Module 2: Male hypogonadism
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Classification of male hypogonadism DHT, dihydrotestosterone Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59;Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Nieschlag
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Classification of male hypogonadism (2) FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/;Hayes F et al. Hypogonadotropic hypogonadism (Hh) and gonadotropin therapy. Endotext. South Dartmouth (MA); 2013.
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Classification of male hypogonadism (3) FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone;SHBG, sex hormone-binding globulin 1. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/2. Grossmann M & Matsumoto AM. J Clin Endocrinol Metab. 2017;102(3):1067–75.3. Tajar A et al. J Clin Endocrinol Metab. 2010;95(4):1810–8. Mixed1 (adult-onset,1 functional2) FSH LH Low testosterone Combined testicular and hypothalamic-pituitary failure, leading to variable gonadotropin secretion
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GnRH, gonadotropin-releasing hormone Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/ Hypogonadism can have avariety of underlying causes The most frequently observed causes of hypogonadism are isolated/idiopathic hypogonadotrophic hypogonadism, hypopituitarism, Klinefelter syndrome and functional hypogonadism Hypogonadism Primary Secondary Target organ resistance Feminization due to androgen resistance or 5α-reductase deficiency Estrogen deficit due to aromatase deficiency Functional hypogonadism Testicular causes Maldescended or ectopic testes Klinefelter syndrome Testicular tumors Orchitis Congenital oracquired anorchia Testicular atrophy/dysgenesis Hypothalamic causes Isolated/idiopathic hypogonadotropic hypogonadism Kallmann syndrome Secondary GnRH deficiency Prader-(Labhart)-Willi syndrome Hypophyseal causes Hyperprolactinemia Hypopituitarism Pituitary tumors
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Causes of hypogonadism Hypo-thalamic Hypo-physeal Secondary to diseases and exogenous toxins Target organ-related Testicular Hypo-thalamic
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FSH, follicle-stimulating hormone;GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Isolated/idiopathic hypogonadotropic hypogonadism and Kallmann syndrome Isolated/idiopathic hypogonadotropic hypogonadism is a genetic disordercaused by insufficient secretion of GnRH from the hypothalamus LH and FSH are not produced by the pituitary gland, so neither androgen synthesis nor spermatogenesis are stimulated in the testes In Kallmann syndrome, a related genetic disorder that occurs in ~1:10,000 males, patients also have anosmia (loss of senseof smell) for aromatic substances e.g. coffee or perfume and may have other physical abnormalities e.g. impaired hearing orcleft palate Hypothalamic causes of hypogonadism Phenotype ofKallmann syndrome
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CDGP, constitutional delay of growth and puberty; GnRH, gonadotropin-releasing hormone Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Delayed puberty Definition: onset of puberty (gonadarche) later than the average age for individuals of the same gender and ethnicity Generally, the onset of puberty is at ~14 years The most common cause of delayed puberty(occurring in up to 1:40 males) is CDGP, in which individual fluctuations in maturation of the hypothalamus delay the initiation of pulsatile GnRH secretion CDGP is an extreme functional variant of the onset of normal puberty; once puberty begins, development is usually normal and ends in complete sexual maturity and normal fertility Hypothalamic causes of hypogonadism Phenotype ofdelayed puberty
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CDGP, constitutional delay of growth and puberty;FSH, follicle-stimulating hormone; LH, luteinizing hormone Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Delayed puberty caused by CDGP does not require treatment It is important to distinguish between CDGP and primary or secondary hypogonadism for prognosis and management: CDGP should not be treated – puberty will start spontaneously However, if the patient is experiencingpsychological pressure because of theirchild-like appearance, short-termtestosterone therapy can be administered This should not begin before 14 yearsof age, because testosterone can causepremature closure of the epiphyseal lines,resulting in reduced stature Hypothalamic causes of hypogonadism Assess gonadotropin and testosterone levels Primary hypogonadism LH and FSH raised Testosterone reduced Secondary hypogonadism LH, FSH and testosterone reduced Open epiphyseal platein boy aged 16 years
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FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Other conditions are associatedwith hypothalamic hypogonadism Prader–(Labhart)–Willi syndrome Genetic disorder associated with mutations and abnormal expression of a cluster of genes on chromosome 15 Affects ~1:10,000 individuals, causing a congenital disturbance of GnRH secretion Pubertal boys with this condition display a specific form of combined secondary (low LH and testosterone) and primary hypogonadism (low inhibin B and high FSH) Anorexia nervosa is associated with low testosterone and gonadotropin levels and poor responses to GnRH stimulation Less common conditions include isolated LH (Pasqualini syndrome) or FSH deficiency, which are exceptionally rare forms of isolated/idiopathic hypogonadotropic hypogonadism, and GnRH deficiency Hypothalamic causes of hypogonadism
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Causes of hypogonadism Hypo-thalamic Hypo-physeal Secondary to diseases and exogenous toxins Target organ-related Testicular Hypo-physeal
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GnRH, gonadotropin-releasing hormone 1. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010.2. Majumdar A & Mangal NS. J Hum Reprod Sci. 2013;6(3):168–75. Hypophyseal hypogonadism is caused by defects in pituitary function With hypophyseal hypogonadism, no increase is seen in gonadotropin secretion after GnRH pump testing, unlike with hypothalamic hypogonadism1 Common causes of hypophyseal hypogonadism include: Hypophyseal causes of hypogonadism Hypo-pituitarism1 Due to hypophyseal insufficiency (a deficiency of one or more pituitary hormones) Most common cause: tumors/metastases of the pituitary and hypophyseal stalk Prolactinomas are the most numerous, followed by endocrine-inactive adenomas, and more rarely, growth hormone-producing adenomas/other tumors Other causes: trauma, infection, hemochromatosis and vascular disorders Hyper-prolactinemia1 Hyperprolactinemia describes any non-physiological increase in prolactin Serum concentrations >20–25 ng/mL (400–500 mU/L) are pathological2 Prolactin reduces hypothalamic GnRH secretion, leading to hypogonadism Hyperprolactinemia is most commonly caused by prolactinomas (prolactin-secreting pituitary adenomas), but it can also be drug-induced (dopamine antagonists) or caused by chronic renal failure or hypothryoidism
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Causes of hypogonadism Hypo-thalamic Hypo-physeal Secondary to diseases and exogenous toxins Target organ-related Testicular Testicular
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Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Primary hypogonadism is causedby defects in testicular function The testes are bi-functional organs, producing both androgens and sperm Hypogonadism may therefore manifest as reduced androgen production and/or disturbed spermatogenesis Disorders of the testes resultin primary hypogonadism, typically characterized by increased gonadotropin and reduced testosterone secretion Testicular causes of hypogonadism
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Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Klinefelter syndrome Klinefelter syndrome is a congenital abnormality of chromosome number that in ~80% of cases has the karyotype of 47,XXY It is the most common form of male hypogonadism (prevalence: 0.2% or 1:500) Clinically, Klinefelter syndrome is characterizedin the adult by the combination of small, firmtestes, infertility, gynecomastia and symptomsof androgen deficiency The signs of Klinefelter syndrome are almost unnoticeable in childhood, and only become apparent after puberty Occasionally, prepubertal boys affected with the condition are referred for testicular maldescentor long-leggedness Phenotype ofKlinefelter syndrome Testicular causes of hypogonadism
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Causes of hypogonadism Hypo-thalamic Hypo-physeal Secondary to diseases and exogenous toxins Target organ-related Testicular Target organ-related
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DHT, dihydrotestosterone Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Target organ-related causesof hypogonadism Hypogonadism can be caused by disorders in which testicular function is intact, but there is impaired action of androgens (testosterone, anti-Müllerian hormone, DHT) and/or estrogens (estradiol) in their target organs This is due to either: Defects or mutations in the corresponding tissue-specific androgen and estrogen receptors (androgen insensitivityor estrogen resistance, respectively) Aberrant 5-reductase activity (e.g. as in perineoscrotal hypospadias with pseudovagina) Deficient aromatase activity (estrogen deficiency) Target organ-related causes of hypogonadism
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Causes of hypogonadism Hypo-thalamic Hypo-physeal Secondary to diseases and exogenous toxins Target organ-related Testicular Secondary to diseases and exogenous toxins
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AIDS, acquired immunodeficiency syndrome; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus 1. Grossmann M & Matsumoto AM. J Clin Endocrinol Metab. 2017;102(3):1067–75. 2. Tajar A et al. J Clin Endocrinol Metab. 2010;95(4):1810–8. 3. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/ 4. Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Secondary causes of hypogonadism Secondary causes of hypogonadism Many systemic conditions and exogenous factors are associated withlow testosterone levels and impairment of testicular or sexual function Obesity is the most-common cause and predictor in middle-aged and older men1,2
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HPT, hypothalamic–pituitary–testicular Grossmann M & Matsumoto AM. J Clin Endocrinol Metab. 2017;102(3):1067–75. Functional hypogonadism is closely linked to obesity and underlying conditions Secondary causes of hypogonadism Many middle-aged and older (age ≥50 years) men, especially those who are obese and/or have underlying conditions, present with clinical features of organic androgen deficiency and modestly (or occasionally severely) low testosterone levels, yet they do not have recognizable intrinsic structural HPT pathology Increasing evidence suggests that in these men, low testosterone is due to functional HPT axis suppression, caused by excess adiposity, comorbid illness and/oruse of medications such as opioids or glucocorticoids
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BMI, body mass index Grossmann M & Matsumoto AM. J Clin Endocrinol Metab. 2017;102(3):1067–75. Functional hypogonadism is closely linked to obesity and underlying conditions (2) Secondary causes of hypogonadism Obesity is the strongest risk factor associated with low testosterone levels in middle-aged and older men In large, prospective, observational studies, weight gain and presence of underlying conditionsare consistently associated with an acceleratedage-related decline in testosterone levels Weight loss can lead to testosterone increasesin obese men
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Rhoden EL & Morgentaler A. N Engl J Med. 2004;350(5):482–92. Hypogonadism: testosterone levelsnaturally decline with age Men with hypogonadism (%) Age (years)
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LH, luteinizing hormone;LHRH, luteinizing hormone-releasing hormone; SHBG, sex hormone-binding globulin; TDS, testosterone deficiency syndrome Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Hypogonadism/TDS: mechanism of down-regulation of testosterone levels Increased sensitivity totestosterone Testicular andhypophyseal-hypothalamic insufficiency prevents an increase in testosterone secretion from the testis Serum SHBG levels increase with age, decreasing the amount of bioactive free testosterone
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Epidemiology Module 2: Male hypogonadism
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Epidemiology of hypogonadism/TDS The prevalence/incidence of hypogonadism/TDS is high; however, estimates differ according to the definition used *Defined as low total (<300 ng/dL) and free (<5 ng/dL) testosterone plus low libido, erectile dysfunction, osteoporosisor fracture, or ≥2 of the following: sleep disturbance, depressed mood, lethargy or diminished physical performanceBACH, Boston Area Community Health; BLSA, Baltimore Longitudinal Study of Aging; HIM, Hypogonadism in Males;MMAS, Massachusetts Male Aging Study; TDS, testosterone deficiency syndrome 1. Mulligan T et al. Int J Clin Pract. 2006;60(7):762–9. 2. Harman SM et al. J Clin Endocrinol Metab. 2001;86(2):724–31.3. Araujo AB et al. J Clin Endocrinol Metab. 2007;92(11):4241–7. 4. Araujo AB et al. J Clin Endocrinol Metab. 2004:89(12); 5920–6. HIM study1 (N=2,126) Men aged ≥45 years (total testosterone <300 ng/mL) Crude prevalence: 38.7% BLSA2 (N=890) Prevalence rates (total testosterone <325 ng/dL) were 12%, 19%, 28% and 49% in men in their 50s, 60s, 70s and 80s, respectively BACH study3 (N=1,475) Men aged 30–79 years Incidence of symptomaticandrogen deficiency*: 5.6% MMAS4 (N=1,691) Men aged 40–70 years with total testosterone <200 ng/dL and ≥3 clinical features of androgen deficiency Prevalence: 12.3%
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N=2,162 men aged ≥45 years visiting US primary care practicesHIM, Hypogonadism in Males; TDS, testosterone deficiency syndrome Mulligan T et al. Int J Clin Pract. 2006;60(7):762–9. HIM study: prevalence of hypogonadism/TDS increases with age Men with hypogonadism (%) Age (years)
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*Tetosterone/SHBG ratio: <0.153 nmol/nmolBLSA, Baltimore Longitudinal Study of Aging; SHBG, sex hormone-binding globulin; TDS, testosterone deficiency syndrome Harman SM et al. J Clin Endocrinol Metab. 2001;86(2):724–31. BLSA study: prevalence of hypogonadism/TDS increases with age Men with hypogonadism (%) Age (years) 20–29 40–49 30–39 50–59 60–69 70–79 ≥80 n= 18 201 279 332 350 251 94
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The daily pattern of male testosterone production is attenuated with age LH, luteinizing hormone Bremner WJ et al. J Clin Endocrinol Metab. 1983;56(6):1278–81; O’Donnell L et al. Endocrinology of the male reproductive system and spermatogenesis. Endotext. South Dartmouth (MA); 2017. Testosterone concentration (ng/mL) 08:00 12:00 16:00 20:00 24:00 08:00 04:00 Time (h) Younger men Older men The testes’ capacity to secrete testosterone declines in ageing men, because of a reduced ability to respond to LH pulses
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SHBG, sex hormone-binding globulin Comhaire FH. Eur Urol. 2000;38(6):655–62. Age-related changes in serum testosterone and SHBG concentrations Serum concentrations Age (years)
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SHBG, sex hormone-binding globulin Vermeulen A. Ann Med. 1993;25(6):531–4. Age-related changes in serum testosterone and SHBG concentrations (2) Serum concentrations Age (years) 8 7 6 5 Free testosterone(nmol/L) Total testosterone(nmol/L) SHBG(10-8 mol/L)
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Clinical signs and symptoms Module 2: Male hypogonadism
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Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/ Symptoms and signs suggestiveof male hypogonadism Male hypogonadism is associated with a wide range of symptoms and signs, some of which are more suggestiveof hypogonadism than others – Most common symptom/sign in aging men
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n=521 men with EDED, erectile dysfunction Guay A et al. J Androl. 2001;22(5):793–7. Erectile dysfunction is associatedwith male hypogonadism Patients (%)
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HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol 1. Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59. 2. Tajar A et al. J Clin Endocrinol Metab. 2010;95(4):1810–8. 3. Giannoulis MG et al. Endocr Rev. 2012;33(3):314–77. Physical and metabolic symptomsand signs of male hypogonadism Physical Often, there are no obvious physical signs; may include decreased muscle mass, loss of body hair, abdominal obesity, gynecomastia and/or small testes (occasionally)1 Obesity is the single most-powerful predictor of low testosterone2 Metabolic and other Reduction in HDL-C and increase in LDL-C3 Impaired glucose metabolism3 Increase in total body fat (change in lean:fat ratio)3 Osteopenia Osteoporosis3 Reduction in red cell volume
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Clinical consequences of hypogonadism are determined by age of onset and severity Androgen deficiency in utero Absence of androgens or androgen deficiency during sexual differentiation (between the 9th and 14th week of pregnancy) leads to intersexuality with incomplete or no masculinization of the external genitalia Lack of or insufficient testosterone exposure in the later phase of development (up to about the 24th week of pregnancy) can also cause malpositioning of the testes and an abnormally small penis (micropenis) Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/
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Clinical consequences of hypogonadism are determined by age of onset and severity (2) Androgen deficiency during puberty When testosterone deficiency occurs before puberty, virilization will not start, resulting in the typical syndrome of eunuchoidism; once the body has taken on eunuchoid proportions, the process is irreversible Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/
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Clinical consequences of hypogonadism are determined by age of onset and severity (3) Androgen deficiency during adulthood With onset after puberty, the clinical picture of hypogonadism can vary widely Body proportions, penis size and pitch of voicedo not change However, body and facial hair dwindle and shavingneed not be carried out as frequently The chief clinical signs are decreased sexual potency, loss of libido and infertility Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/
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Diagnosis Module 2: Male hypogonadism
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COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; TDS, testosterone deficiency syndrome Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/ Patient selection Diagnosis of male hypogonadism is based on persistent signs and symptoms of androgen deficiency, plus consistently low serum testosterone concentrations Assessment of TDS should also be considered in men with underlying conditions or who are receiving treatments that are commonly associated with male hypogonadism
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AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; BMI, body mass index Garvey WT et al. Endocr Pract. 2016;22 Suppl 3:1–203. Special guidance for overweight orobese men with suspected hypogonadism
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History-taking and physical examination of adult men with suspected hypogonadism Dean JD et al. J Sex Med. 2015;12(8):1660–86; Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/; Lunenfeld B et al. Aging Male. 2015;18(1):5–15;Petak SM et al. Endocr Pract. 2002;8(6):439–56.
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Clinical assessment of male hypogonadism The most widely accepted diagnostic parametersfor male hypogonadism are serum total testosterone and free testosterone1–3 Clinical assessment of testosterone deficiency syndrome includes symptoms and biochemical confirmation with low circulating testosterone concentrations1–3 1. Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59. 2. Dean JD et al. J Sex Med. 2015;12(8):1660–86.3. Lunenfeld B et al. Aging Male. 2015;18(1):5–15.
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Testosterone level cut-offs There is no universally accepted lower limit of ‘normal’ for testosterone level, and it is unclear whether geographically different thresholds depend on ethnic differences or the clinician’s perception1,2 However, there is general agreement that:1–6 *Consider TTh in individual cases, based on total T concentrations/symptoms and low calculated free T concentrations6SHBG, sex hormone-binding globulin; T, testosterone; TDS, testosterone deficiency syndrome; TTh, testosterone therapy 1. Nieschlag E et al. J Androl. 2006;27(2):135–7. 2. Dean JD et al. J Sex Med. 2015;12(8):1660–86.3. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/4. Lunenfeld B et al. Aging Male. 2015;18(1):5–15. 5. Hackett G et al. Int J Clin Pract. 2017;71(3–4):e12901.6. Traish AM et al. Am J Med. 2011;124(7):578–87. TDS unlikely Consider TTh* Total T<8 nmol/L (231 ng/dL) or Free T<180 pmol/L (5.2 ng/dL) TDS likely TTh indicated Total T8–12 nmol/L (231–346 ng/dL) or Free T180–225 pmol/L (5.2–6.5 ng/dL) TDS possible, consider TTh(if presence of bothersome symptoms and/or elevated SHBG) Total T >12 nmol/L (346 ng/dL) or Free T>225 pmol/L (6.5 ng/dL)
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Biochemical examination of adult men with suspected hypogonadism Basic hormonal examinations for male hypogonadism include assessment of testosterone, LH and FSH Testosterone reveals the endocrine activity of the testes LH and FSH are indicators of pituitary function and allow etiological assessment of hypogonadism Increased gonadotropins indicate primary hypogonadism Decreased gonadotropins in combination with decreased testosterone suggest secondary hypogonadism Other hormonal assays and baseline tests may include SHBG, hematocrit and lipid profile FSH, folllicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone-binding globulin Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59; Petak SM et al. Endocr Pract. 2002;8(6):439–56.
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Recommendations onmeasuring testosterone levels Measure total testosterone between 07:00–11:001–4 Serum testosterone levels exhibit a circadian variationwith peak values in the morning between 06:00–08:00and a nadir between 18:00–20:002,3 Clinical symptoms of hypogonadism may be less clearin older individuals because of blunting of the diurnalvariation of testosterone secretion and otherage-related changes2,3 If testosterone levels are below or at the lower limitof accepted normal adult male values [e.g. total testosterone <12 nmol/L (346 ng/dL)], a second measurement of total and/or free testosterone, together with LH and prolactin(and SHBG, in obese and older men) should be performed1–4 LH, luteinizing hormone; SHBG, sex hormone-binding globulin 1. Dean JD et al. J Sex Med. 2015;12(8):1660–86. 2. Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59.3. Lunenfeld B et al. Aging Male. 2015;18(1):5–15. 4. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/
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Analytical methods formeasuring total testosterone CLIA, chemiluminescent immunoassay; ELISA, enzyme-linked immunosorbent assay; GC, gas chromatography;LC, liquid chromatography; RIA, radioimmunoassay; T, testosterone 1. Rosner W et al. J Clin Endocrinol Metab. 2007;92(2):405–13. 2. Dean JD et al. J Sex Med. 2015;12(8):1660–86.
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Analytical methods for measuringfree or bioavailable testosterone RIA, radioimmunoassay; SHBG, sex hormone-binding globulin; T, testosterone Rosner W et al. J Clin Endocrinol Metab. 2007;92(2):405–13; Dean JD et al. J Sex Med. 2015;12(8):1660–86.
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Nebido.com: Online tools for testosterone estimation and calculation https://www.nebido.com/en/hcp/research/testosterone-tools/
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Questionnaires for hypogonadism screening and outcome measurement Several patient- and clinician-reported instruments exist for hypogonadism screening and outcome measurement These questionnaires may assist: Assessment of symptoms prior to starting TTh Monitoring of clinical response to TTh during follow-up Patient adherence to TTh Clinical documentation ADAM, Androgen Deficiency in the Aging Male (https://www.nebido.com/en/patients/check-yourself/adam-test/);AMS, Aging Male’s Symptoms scale (https://www.nebido.com/en/hcp/your-patients/ams-questionnaire-tool/);MMAS, Massachusetts Male Aging Study; TTh, testosterone therapy Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59; Dean JD et al. J Sex Med. 2015;12(8):1660–86;Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/; Lunenfeld B et al. Aging Male. 2015;18(1):5–15. ADAM AMS MMAS
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ADAM questionnaire ADAM, Androgen Deficiency in the Aging Male Morley JE et al. Metabolism. 2000;49(9):1239–42. Low testosterone may be suspected if the answer to questions 1 or 7, or any 3 other questions is ‘Yes’
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AMS questionnaire (part 1) AMS, Aging Male’s Symptoms scale http://zeg-berlin.de/expertise/diagnostics-tools/aging-male-symptoms-scale/self-assessment/
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AMS questionnaire (part 2) AMS, Aging Male’s Symptoms scale http://zeg-berlin.de/expertise/diagnostics-tools/aging-male-symptoms-scale/self-assessment/
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MRI, magnetic resonance imaging; PDE -5, phosphodiesterase type 5; PSA, prostate-specific antigen;SHBG, sex hormone-binding globulin; T, testosterone; TTh, testosterone therapy Traish AM et al. Am J Med. 2011;124(7):578–87. Diagnostic evaluation of adult menwith suspected hypogonadism Assess free T Assess total T Consider ≥1 of the following tests, depending on the clinical situation: Gonadotropins, free T Prolactin, estradiol Thyroid and adrenal axes Stimulation test of pituitary gland Karyotype, fertility status Testicular ultrasound MRI of pituitary gland/hypothalamus Possible co-operation with an andrologist or endocrinologist Clinical symptoms/signsof testosterone deficiency Presence of ≥1 componentsof the metabolic syndrome Erectile dysfunction Total T <8 nmol/L(<250 ng/dL) Total T 8–12 nmol/L(250–350 ng/dL) Total T >12 nmol/L(>350 ng/dL) Free T <270 pmol/L(<8 ng/dL) Proceed with trial of TTh (after exclusionof contraindications) Follow-up visit at 3 and 6–12 months thereafter: Efficacy of treatment? Hematocrit and PSA normal? Add PDE-5 inhibitor?
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Associated comorbiditiesand burden of disease Module 2: Male hypogonadism
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Giannoulis MG et al. Endocr Rev. 2012;33(3):314–77;Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Health consequencesof male hypogonadism Hypogonadism is associated with several underlying conditions, including: Cardiovascular disease Diabetes Obesity and the metabolic syndrome Osteoporotic fracture It is often also associated with pronounced disturbanceson quality of life and detrimental effects on multipleorgan systems, including reduced general well-being, depression, diminished physical strength, andsexual dysfunction
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Maggio M & Basaria S. Int J Impot Res. 2009;21(4):261–4. Low androgen levels are associatedwith many cardiovascular risk factors Cardiovascular disease Insulin resistance Vascular stiffness Metabolic syndrome Atherosclerosis Hypertension Dyslipidemia Inflammation Diabetes Male hypogonadism Mortality
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ADAM, Androgen Deficiency in the Aging Male; CHD, coronary heart disease 1. Buvat J et al. J Sex Med. 2010;7(4 Pt 2):1627–56. 2. Pugh PJ et al. Endocrine Abstracts. 2003;5:P225. 3. Hak AE et al. J Clin Endocrinol Metab. 2002;87(8):3632–9. 4. van den Beld AW et al. Am J Epidemiol. 2003;157(1):25–31. Male hypogonadism is an independent biomarker for cardiovascular disease Among studies that assessed the relationship between testosterone and CHD, approximately half found an association with hypogonadism in these patients1 Levels of total and/or bioavailable testosterone are significantly reduced in men with CHD2 Approximately 1 in 4 men with CHD (23.4%) in the SouthYorkshire Study had serum testosterone levels within the clinically hypogonadal range (ADAM questionnaire symptom scores were positive in 93.5%) Low serum testosterone levels are associated with atherosclerosis in men3,4 Cardiovascular disease
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n=831 men with proven CHDCHD, coronary heart disease; T, testosterone Pugh PJ et al. J Am Col Cardiol. 2003;41:344A. The South Yorkshire Study: hypogonadismis prevalent in men with coronary heart disease Cardiovascular disease Number of patients (%)
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*p<0.001, **p<0.05 versus healthy controlsCAD, coronary artery disease; SHBG, sex hormone-binding globulin Dunajska K et al. Aging Male. 2004;7(3):197–204. Men with coronary artery disease have lower testosterone levels than healthy men Measurement Men with CAD (n=56) Healthy controls (n=30) ** ** ** * ** Totaltestosterone/ estradiol ratio Cardiovascular disease
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*Adjusted for age; **Adjusted for age, body mass index, systolic blood pressure; cholesterol level, high-density lipoprotein cholesterol level; diabetes mellitus (yes/no), smoking history (ever/never) and alcohol intake (4 categories)n=504 non-smoking men aged ≥55 yearsCI, confidence interval Hak AE et al. J Clin Endocrinol Metab. 2002;87(8):3632–9. The Rotterdam Study: low testosterone increases atherosclerosis risk in elderly men Cardiovascular disease Relative risk (95% CI) 0.5 2.0 0–9.8 >9.8–12.6 >12.6–36.8 Total testosterone (nmol/L): 0–5.6 >5.6–7.5 >7.5–28.7 Bioavailable testosterone (nmol/L): Decreased risk Increased risk p=0.03 p=0.04 p=0.006 p=0.004
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CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol Traish AM et al. J Androl. 2009;30(5):477–94. Low testosterone in men is associated with abnormal lipid profiles Both androgen deficiency and androgen excess in men are associated with an unfavorable lipid profile and increased CV risk:1 Androgen deficiency: increased levels of total cholesterol and LDL-C, increased production of pro-inflammatory factors, increased thicknessof the arterial wall Androgen excess: decreased levels of HDL-C Maintaining androgen levels in the physiological range promotesa favorable lipid profile and has potential benefits for CV health1 Restoration of arterial vasoreactivity, reduction in levels oftotal cholesterol, triglycerides and pro-inflammatory cytokines, improvement in endothelial function Cardiovascular disease
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*p<0.001, **p<0.01, ***p<0.04 versus men with normal total THDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; T, testosterone Simon D et al. J Clin Endocrinol Metab. 1997;82(2):682–5. The Telecom Study: low testosterone in men is associated with an unfavorable lipid profile Mean concentration (mmol/L) Healthy, adult menwith low total T (n=25) Healthy, adult menwith normal total T (n=25) * *** ** ** Cardiovascular disease
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CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol National Heart, Lung, and Blood Institute. What is Metabolic Syndrome? 2016.https://www.nhlbi.nih.gov/health/health-topics/topics/ms What is metabolic syndrome? Metabolic syndrome is a cluster of the most critical risk factors for developing CHD, stroke and type 2 diabetes Components of metabolic syndrome include: Abdominal obesity Dyslipidemia Particularly hypertriglyceridemia and decreased HDL-C levels Hypertension Raised fasting plasma glucose levels Insulin resistance Metabolic syndrome & diabetes
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International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. 2006. https://www.idf.org/e-library/consensus-statements/60-idfconsensus-worldwide-definitionof-the-metabolic-syndrome.html Metabolic syndrome is the ‘tip of the iceberg’ heralding serious underlying conditions Metabolic syndrome & diabetes Metabolic syndrome 10–15 years Atherosclerosis Pro-inflammatory state Pro-thrombotic state Hypertension Dyslipidemia Glucose intolerance Hyperinsulinemia Insulin resistance Abdominal obesity
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*If body mass index is >30 kg/m2, central obesity is assumed and waist circumference does not need to be measuredHDL-C, high-density lipoprotein cholesterol; IDF, International Diabetes Federation; OGTT, oral glucose tolerance test International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. 2006. https://www.idf.org/e-library/consensus-statements/60-idfconsensus-worldwide-definitionof-the-metabolic-syndrome.html IDF definition of metabolic syndrome Metabolic syndrome & diabetes
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Traish AM et al. J Androl. 2009;30(1):23–32. Relationship between hypogonadism and key components of the metabolic syndrome Metabolic syndrome & diabetes Hypogonadism (androgen/testosterone deficiency) Metabolic syndrome Hyper-glycemia Obesity Insulin resistance Hypertension Dyslipidemia
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*Adjusted for age category; **Adjusted for age category, smoking history, alcohol consumption, CVD and adulthood socioeconomic status; ***Adjusted for factors in Model 2 plus body mass indexn=1,865 non-diabetic, middle-aged menCI, confidence interval Laaksonen DE et al. Eur J Endocrinol. 2003;149(6):601–8. The presence of metabolic syndrome is more likely with lower testosterone levels Odds ratio (95% CI) 23.4–51.7 17.0–23.3 1.1–16.9 Total testosterone (nmol/L): 332–717 266–331 10–265 Free testosterone (pmol/L): Lower odds Higher odds p<0.001 p=0.002 p<0.001 p=0.008 Metabolic syndrome & diabetes 0.5 5.0 p<0.001 p<0.001
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*p<0.001 versus men with optimal waist circumference (<94.0 cm)n=1,548 community-dwelling men aged 25–84 years who took part in the 1994–95 survey of the Tromsø studyT, testosterone Svartberg J et al. Eur J Epidemiol. 2004;19(7):657–63. The Tromsø study: waist circumference correlates with total testosterone levels Total T concentration (nmol/L) Waist circumference (cm) * Reference range Metabolic syndrome & diabetes
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Metabolic syndrome & diabetes Courtesy of Professor T. Hugh Jones, University of Sheffield Medical School, Sheffield, UK. Waist circumference correlates with bioavailable testosterone levels Waist circumference (cm) Bioavailable testosterone (nmol/L) 1 2 3 4 5 6 7 8 9 10 11 r= -0.21; p<0.001
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FFA, free fatty acid; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor-1; TNFα, tumor necrosis factor alpha Eckel RH et al. Lancet. 2005;365(9468):1415–28;Lyon CJ et al. Endocrinology. 2003;144(6):2195–200; Trayhurn P & Wood IS. Br J Nutr. 2004;92(3):347–55. Visceral fat is an active endocrine organ Adiposetissue ↑ IL-6 ↓ Adiponectin ↑ Leptin ↑ TNFα ↑ Adipsin(Complement D) ↑ PAI-1 ↑ FFA ↑ Insulin ↑ Angiotensinogen ↑ Lipoprotein lipase ↑ Lactate Inflammation Type 2diabetes Hypertension Atherogenicdyslipidemia Thrombosis Atherosclerosis ↑Resistin Metabolic syndrome & diabetes
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IL-6, interleukin-6; LH, luteinizing hormone; TNFα, tumor necrosis factor alpha Eckel RH et al. Lancet. 2005;365(9468):1415–28;Lyon CJ et al. Endocrinology. 2003;144(6):2195–200; Trayhurn P & Wood IS. Br J Nutr. 2004;92(3):347–55. The Hypogonadal–Obesity–Adipocytokine Hypothesis Metabolic syndrome & diabetes Adiposetissue – + – – – + ↑ Triglyceride uptake ↑ Lipoprotein lipase activity ↑ Adipocyte number and size ↓ Testosterone ↑ Insulin resistance Estradiol TNFα IL-6 Leptin Hypothalamic-pituitary axis ↓LH pulse amplitude Testis Aromatase
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HbA1c, glycated hemoglobin; SHBG, sex hormone-binding globulin 1. Traish AM et al. J Androl. 2009;30(1):10–22. 2. Traish AM et al. J Androl. 2009;30(1):23–32.3. Stellato RK et al. Diabetes Care. 2000;23(4):490–4. 4. Laaksonen DE et al. Diabetes Care 2004;27(5):1036–41. Low testosterone is associated with metabolic syndrome and diabetes in men Hypogonadal men are at increased risk of developing metabolic syndrome and type 2 diabetes1,2 In men, androgen deficiency (low testosterone, SHBG) precedes elevations in fasting insulin, glucose and HbA1c levels and may even predict the onset of metabolic syndrome and diabetes2–4 Androgen deficiency is associated with metabolic syndrome, insulin resistance, type 2 diabetes and increased deposition of visceral fat2 The latter can serve as an endocrine organ, secreting inflammatory cytokines, thus promoting endothelial dysfunction and subsequent development of cardiovascular disease2 Metabolic syndrome & diabetes
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n=355 men with type 2 diabetes (mean age: 58 years)T, testosterone Kapoor D et al. Diabetes Care. 2007;30(4):911–7. Prevalence of hypogonadism by agein men with type 2 diabetes Metabolic syndrome & diabetes
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CI, confidence interval;MMAS, Massachusetts Male Aging Study; RR, relative risk; SD, standard deviation; SHBG, sex hormone-binding globulin 1. Stellato RK et al. Diabetes Care. 2000;23(4):490–4. 2. Laaksonen DE et al. Diabetes Care. 2004;27(5):1036–41. Male hypogonadism is associated with increased risk of metabolic syndrome and diabetes Metabolic syndrome & diabetes
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Incidence of diabetesat 9-year follow-up (%) Patient subgroup T, testosterone 1. Stellato RK et al. Diabetes Care. 2000;23(4):490–4. 2. Laaksonen DE et al. Diabetes Care. 2004;27(5):1036–41. Male hypogonadism is associated with increased incidence of type 2 diabetes Metabolic syndrome & diabetes Incidence of diabetesat 11-year follow-up (%) Patient subgroup
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1. Willson T et al. Clin Epidemiol. 2015;7:65–76. 2. Golds G et al. Int J Endocrinol. 2017;2017:4602129. Osteoporosis is a common and important underlying condition in older men Up to 25% of men aged >50 years will have at least 1 osteoporosis-related fracture in their lifetime1 Hip fractures contribute to the greatest morbidity and mortality in men1 Each year, ~80,000 men will break their hip; of these, one-third will die within the first year after the break, and another one-third will have a repeat fracture Morbidity and mortality associatedwith male hip fractures are greater than those for female hip fractures2 Men with known fragility fracturesare less likely to receive treatment than women2 Osteoporosis Patients (%) Age (years)
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ADT, androgen deprivation therapy 1. Golds G et al. Int J Endocrinol. 2017;2017:4602129. 2. Willson T et al. Clin Epidemiol. 2015;7:65–76. Hypogonadism is a common cause of secondary osteoporosis in men As well as aging, ~50% of men have anotherattributable cause for their osteoporosis1 These secondary causes include chronic disease,alcohol abuse, excess glucocorticoids and hypogonadism(both idiopathic and through ADT)2 Hypogonadism is responsible for 16–30% of casesof secondary osteoporosis in men1 Osteoporosis
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BMD, bone mineral density Golds G et al. Int J Endocrinol. 2017;2017:4602129. Hypogonadism can cause male osteoporosis and contribute to associated morbidity Adult male hypogonadism is associatedwith a decline in BMD and is correlatedwith increased fracture risk Testosterone has a clear, direct effect on bone health: Androgen receptor signalling directly stimulates osteoblasts to form trabecular bone and helps osteocytes to prevent trabecular bone loss Indirectly, it has inhibitory effects on bone resorption via aromatization to estradiol It independently maintains muscle strengthand physical performance This likely reduces the risk of falls and associated fracture, and contributes to maintenance of BMD and bone health Osteoporosis
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*p=0.003 versus men with hip fracturesN=56 men with current or history of hip fractures (n=28) and age-, athnicity- and living status-matched controls (n=28) Jackson JA et al. Am J Med Sci. 1992;304(1):4–8. Hypogonadism is a risk factorfor hip fractures in men Osteoporosis Presence of hypogonadism (%) *
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CV, cardiovascular; T, testosterone 1. Shores MM et al. Arch Intern Med. 2006;166(15):1660–5.2. Araujo AB et al. J Clin Endocrinol Metab. 2011;96(10):3007–19. Hypogonadism is associated with increased risk of death in men Hypogonadism appears to lower life expectancy1,2 In a US study of men aged >40 years (N=858), those with normal T levels had a mortality rate of 20.1%, compared with 34.9% in men with low T levels[total testosterone: >8.7 nmol/L (>250 ng/dL) orfree testosterone: <0.03 nmol/L (0.75 ng/dL)] over a mean follow-up of 4.3 years1 Low testosterone increased mortality risk by 88%1 Low testosterone levels are associated with increased risk of all-cause and CV death2 Mortality
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Hypogonadism is associated with increased risk of death in men Mortality *p<0.001 versus normal testosterone levels**Adjusted for age, medical morbidity, body mass index, and glucocorticoid and opiate treatmentn=858 men aged >40 yearsCI, confidence interval Shores MM et al. Arch Intern Med. 2006;166(15):1660–5.
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BPH, benign prostatic hyperplasia; QoL, quality of life; SF-12, 12-Item Short Form Survey; SF-36, 36-Item Short Form Survey 1. Bhasin S et al. J Clin Endocrinol Metab. 2010;95(6):2536–59. 2. Finas D et al. Andrologia. 2006;38(2):48–53. Male hypogonadism is associated with decreased physical function and vitality Few studies have investigated the effect of hypogonadism on QoL despite its potential negative impact on sexual function, energy levels, body composition, mood and cognitive function1 In a study comparing 24 men aged >50 years with BPH treatedwith surgery and subnormal free testosterone concentrations(<200 pmol/L) with 24 age-matched controls, health-related QoL was assessed using the SF-12 Health Survey and the psychological well-being components of the SF-36 scale2 Vitality and physical symptom scores were significantly worse in patients with low testosterone, compared with age-matched controls (p<0.05)2 No statistically significant difference was observed in the mental health index or in measures of psychological well-being2
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*Adjusted for age, ethnicity, number of clinic visits, alcohol use disorders, prostate cancer and Chronic Disease Score**Adjusted for age and medical comorbidityCI, confidence interval; HR, hazard ratio; ICD-9, International Classification of Diseases, 9th Revision, Clinical Modification 1. Shores MM et al. Arch Gen Psychiatry. 2004;61(2):162–7. 2. Shores MM et al. J Clin Psychiatry. 2005;66(1):7–14. Male hypogonadism is associated withearlier onset and increased risk of depression Depression
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Depression Incidence of depressionat 2-year follow-up (%) Patient subgroup T, testosterone 1. Shores MM et al. Arch Gen Psychiatry. 2004;61(2):162–7. 2. Shores MM et al. J Clin Psychiatry. 2005;66(1):7–14. Male hypogonadism is associated with increased incidence of depression Incidence of depressionat 2-year follow-up (%) Patient subgroup
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*p<0.05 versus eugonadal menN=278 men aged ≥45 years visiting US primary care practices Shores MM et al. Arch Gen Psychiatry. 2004;61(2):162–7. Incident depression increases with greater severity of hypogonadism 2-year depression incidence Total testosterone level * * * Declining testosterone level Depression
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1. Slagter SN et al. PLoS One 2015;10(10):e0149588. 2. Edward KL et al. Am J Mens Health. 2018;12(2):265–73.3. Herman WH. Diabetes Care. 2013;36(4):775–6. Untreated hypogonadism is associated with substantial personal and societal costs Hypogonadism carries an increased risk of certain underlying conditions, which can have a substantial economic burden and detrimental effect on quality of life, for example:
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ED, erectile dysfunction; PDE-5, phosphodiesterase type 5; TDS, testosterone deficiency syndrome Maggi M et al. J Sex Med. 2007;4(4 Pt 1):1056–69. Untreated hypogonadism is associated with substantial personal and societal costs Hypogonadism carries an increased risk of certain underlying conditions, which can have a substantial economic burden and detrimental effect on quality of life, for example:
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Summary The majority of international societies have definedmale hypogonadism as a clinical syndrome caused by androgen deficiency, which can adversely affect the function of multiple organ systems and quality of life Male hypogonadism may be caused by defects inthe testis (primary), hypothalamus/pituitary gland (secondary) or both (mixed/adult-onset/functional),as well as target organ androgen insensitivity/resistance and disease or toxins Subclinical hypogonadism associated with aging (compensated hypogonadism) is also recognized as a distinct clinical entity
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Summary (2) The prevalence/incidence of male hypogonadism is high and increases with age Male hypogonadism is associated with a variety of symptoms and signs The most common in aging men are reduced sexual desireand activity, erectile dysfunction, type 2 diabetes mellitus,loss of vigor, mood changes and poor general health status Obesity is the single most-powerful predictor of low testosterone A diagnosis of male hypogonadism comprises persistent clinical symptoms plus biochemical evidence of consistently low serum testosterone concentrations Assessment of TDS should also be considered in men with obesity, type 2 diabetes mellitus and/or other underlying conditions or who are receiving treatments commonly associated with male hypogonadism TDS, testosterone deficiency syndrome
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Summary (3) Male hypogonadism commonly occurs with several underlying conditions, including obesity, metabolic syndrome, cardiovascular disease, diabetes and osteoporotic fracture It is also associated with: Decreased quality of life Marked detrimental effects on general well-being,physical strength and sexual function Depression Increased risk of mortality Substantial societal costs