Approval Number GMKTGMMH0420180513 Definition Module 2 Male hypogonadism Several international societies have proposed definitions of hypogonadism Guideline Definition EAU guidelines ID: 774641
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Slide1
Module 2
Male hypogonadism
Approval
Number
: G.MKT.GM.MH.04.2018.0513
Slide2Definition
Module 2: Male hypogonadism
Slide3Several international societies have proposed definitions of hypogonadism
GuidelineDefinitionEAU guidelines1(2017)Male hypogonadism is a clinical syndrome caused by androgen deficiency which may adversely affect multiple organ functionsand quality of lifeA diagnosis of male hypogonadism must comprise bothpersistent clinical symptoms and biochemical evidence of testosterone deficiencyEndocrine Society clinical practice guideline2(2010)Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis
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.
Slide4Several international societies have proposed definitions of hypogonadism (2)
GuidelineDefinitionISSAM recommendations(2015)Hypogonadism (testosterone deficiency) in adult men is a clinical and biochemical syndrome associated with low level of testosterone, which may adversely affect multiple organ functions and quality of lifeAlthough the clinical significance of hypogonadism in adult men is becoming increasingly recognized, the extent of its prevalence in the general population is underappreciatedA large number of men with hypogonadism remain undiagnosedand untreated
ISSAM
, International Society for the Study of the Aging
Male
Lunenfeld
B et al. Aging Male. 2015;18(1):5–15.
Slide5Several international societies have proposed definitions of hypogonadism (3)
GuidelineDefinition4th ICSM recommendations(2015)TD is a clinical AND a biochemical syndrome associated with age and comorbidities and characterized by a deficiency in testosterone AND relevant symptomsTD can affect the function of multiple organ systems and result in significant detriment in quality of life, including alterations in sexual functionTD results from defects at various levels of the hypothalamus-pituitary-testis axis: abnormality in the testes (primary TD), pituitary or hypothalamic failure (secondary TD), or a combination of the two (mixed TD)TD can also result from an impairment of testosterone action because of decreased bioavailability of the hormone (owing to SHBG variations) or because of androgen receptor alterations that can influence androgen activityThe clinical manifestations of TD occur as a result of decreased serum androgen concentrations or activity, regardless of whether there is an identified underlying etiology
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.
Slide6Several international societies have proposed definitions of hypogonadism (4)
GuidelineDefinitionISSM processof care(2015)ISSM recommends that the term “testosterone deficiency” is universally adopted and used in clinical practice, along with the following definition:Testosterone deficiency is a clinical and biochemical syndrome characterized by a deficiency of testosterone,or testosterone action, and relevant symptoms and signsTD may affect the function of multiple organ systems, and result in significant detriment in the quality of life, including alterations in sexual function
ISSM, International Society for Sexual Medicine; TD, testosterone deficiency
Dean JD
et al. J
Sex Med. 2015;12(8):1660–86.
Slide7Classification and etiology
Module 2: Male hypogonadism
Slide8Classification of male hypogonadism
DHT, dihydrotestosteroneBhasin 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.
Primary
hypogonadism
Secondary
hypogonadism
Target organ
androgen insensitivity/
resistance
Androgen receptor defect
5α-reductase deficiencyAromatase deficiency
Testis
HypothalamusPituitary gland
Target tissuesfor testosterone,DHT and estradiol
Nieschlag
Slide9Classification of male hypogonadism (2)
FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormoneDohle 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.
Pituitary
gland
Hypothalamus
Testis
No
hypogonadism
GnRH
+
FSH
LH
Normal
testosterone
Normal hypothalamic-
pituitary-testicular function
Low testosterone
Hypothalamic-pituitary
failure
with
decreased
gonadotropin secretion
Secondary
FSH
LH
Low testosterone
Testicular failure
with
elevated
gonadotropin secretion
Primary
GnRH
+
FSH
LH
Slide10Classification of male hypogonadism (3)
FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone;SHBG, sex hormone-binding globulin1. 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.
Mixed
1
(adult-onset,
1
functional
2
)
FSH
LH
Low testosterone
Combined
testicular and hypothalamic-pituitary failure, leading to
variable gonadotropin
secretion
Normal testosterone
Elevated LH secretion
Elevated SHBG secretion
(lower free testosterone)
Associated predominantly
with physical symptoms
Compensated
3
(subclinical)
GnRH
+
FSH
LH
Slide11GnRH, gonadotropin-releasing hormoneDohle 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 deficiencyEstrogen deficit due to aromatase deficiency
Functional hypogonadism
Testicular causes
Maldescended
or ectopic testesKlinefelter syndromeTesticular tumorsOrchitisCongenital oracquired anorchiaTesticular atrophy/dysgenesis
Hypothalamic causes
Isolated/idiopathic hypogonadotropic hypogonadism
Kallmann syndromeSecondary GnRH deficiencyPrader-(Labhart)-Willi syndrome
Hypophyseal
causes
HyperprolactinemiaHypopituitarismPituitary tumors
Slide12Causes of hypogonadism
Hypo-thalamic
Hypo-
physeal
Secondary to diseases and exogenous toxins
Target organ-related
Testicular
Hypo-thalamic
Slide13FSH, follicle-stimulating hormone;GnRH, gonadotropin-releasing hormone; LH, luteinizing hormoneNieschlag 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 hypothalamusLH and FSH are not produced by the pituitary gland, so neither androgen synthesis nor spermatogenesis are stimulated in the testesIn 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 of
Kallmann
syndrome
Slide14CDGP, constitutional delay of growth and puberty; GnRH, gonadotropin-releasing hormoneNieschlag 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 ethnicityGenerally, the onset of puberty is at ~14 yearsThe 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 secretionCDGP 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 of
delayed puberty
Slide15CDGP, constitutional delay of growth and puberty;FSH, follicle-stimulating hormone; LH, luteinizing hormoneNieschlag 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 spontaneouslyHowever, if the patient is experiencingpsychological pressure because of theirchild-like appearance, short-termtestosterone therapy can be administeredThis 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 plate
in boy aged 16 years
Slide16FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormoneNieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010.
Other conditions are associatedwith hypothalamic hypogonadism
Prader–(Labhart)–Willi syndromeGenetic disorder associated with mutations and abnormal expression of a cluster of genes on chromosome 15Affects ~1:10,000 individuals, causing a congenital disturbance of GnRH secretionPubertal 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 stimulationLess 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
Slide17Causes of hypogonadism
Hypo-thalamic
Hypo-
physeal
Secondary to diseases and exogenous toxins
Target organ-related
Testicular
Hypo-
physeal
Slide18GnRH, gonadotropin-releasing hormone1. 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 hypogonadism1Common causes of hypophyseal hypogonadism include:
Hypophyseal
causes
of hypogonadism
Hypo-pituitarism
1
Due to hypophyseal insufficiency (a deficiency of one or more pituitary hormones)Most common cause: tumors/metastases of the pituitary and hypophyseal stalkProlactinomas are the most numerous, followed by endocrine-inactive adenomas, and more rarely, growth hormone-producing adenomas/other tumorsOther causes: trauma, infection, hemochromatosis and vascular disorders
Hyper-prolactinemia
1
Hyperprolactinemia
describes any non-physiological increase in prolactin
Serum concentrations
>20–25 ng/mL (400–500
mU
/L) are
pathological
2
Prolactin
reduces hypothalamic GnRH secretion,
leading to
hypogonadism
H
yperprolactinemia 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
Slide19Causes of hypogonadism
Hypo-thalamic
Hypo-
physeal
Secondary to diseases and exogenous toxins
Target organ-related
Testicular
Testicular
Slide20Nieschlag 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 spermHypogonadism may therefore manifest as reduced androgen production and/or disturbed spermatogenesisDisorders of the testes resultin primary hypogonadism, typically characterized by increased gonadotropin and reduced testosterone secretion
Testicular causes
of
hypogonadism
Conditions
and t
esticular defects associated
with primary hypogonadism include:
Congenital or
acquired
anorchidism
Male
pseudohermaphroditism
Maldescended
testes
Orchitis
Klinefelter
syndrome
XX Male syndrome
Testicular tumors
Slide21Nieschlag 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,XXYIt 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 deficiencyThe signs of Klinefelter syndrome are almost unnoticeable in childhood, and only become apparent after pubertyOccasionally, prepubertal boys affected with the condition are referred for testicular maldescentor long-leggedness
Phenotype of
Klinefelter
syndrome
Testicular causes
of
hypogonadism
Slide22Causes of hypogonadism
Hypo-thalamic
Hypo-
physeal
Secondary to diseases and exogenous toxins
Target organ-related
Testicular
Target organ-related
Slide23DHT, dihydrotestosteroneNieschlag 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 organsThis 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
Slide24Causes of hypogonadism
Hypo-thalamic
Hypo-
physeal
Secondary to diseases and exogenous toxins
Target organ-related
Testicular
Secondary
to diseases and exogenous toxins
Slide25AIDS, acquired immunodeficiency syndrome; COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus1. 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
Other systemic conditions include:3,4Critical illnessType 2 diabetes mellitusKidney diseaseand acute renal failureGastrointestinal diseasesEpilepsyHemochromatosisCancerHypertensionRheumatoid arthritisMultiple sclerosisCOPDLiver cirrhosis, liver disease and chronic liver failureSickle cell diseaseLeprosyHIV infection and AIDSSystemic illness/infectionExogenousfactors include:3,4Drugs and medicatione.g. chronic opioid use, glucocorticoid therapyRadiationEnvironmental toxinsHeat
Many systemic conditions and exogenous factors are associated
with
low
testosterone levels and impairment of testicular or sexual function
Obesity
is the most-common cause and predictor
in middle-aged and older
men
1,2
Slide26HPT, hypothalamic–pituitary–testicularGrossmann 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 ye
ars) 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/or
use of medications such as opioids or glucocorticoids
Slide27BMI, body mass indexGrossmann 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 menIn large, prospective, observational studies, weight gain and presence of underlying conditionsare consistently associated with an acceleratedage-related decline in testosterone levelsWeight loss can lead to testosterone increasesin obese men
Total testosterone increase
(
nmol
/L)
Body weight loss (% of total)
Diet/exercise
Bariatric surgery
Slide28Rhoden EL & Morgentaler A. N Engl J Med. 2004;350(5):482–92.
Hypogonadism: testosterone levelsnaturally decline with age
Men with hypogonadism (%)
Age (years)
Slide29LH, luteinizing hormone;LHRH, luteinizing hormone-releasing hormone; SHBG, sex hormone-binding globulin; TDS, testosterone deficiency syndromeNieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010.
Hypogonadism/TDS: mechanism of down-regulation of testosterone levels
Increased
sensitivity to
testosterone
Testosterone
SHBG
Testosterone
SHBG
Reduced
LHRH
Reduced
LH
Pituitary
gland
Hypothalamus
Testis
Testicular
and
hypophyseal
-hypothalamic
insufficiency prevents an increase in testosterone
secretion from
the testis
Serum SHBG levels increase with age, decreasing the amount of bioactive free testosterone
Slide30Epidemiology
Module 2: Male hypogonadism
Slide31Epidemiology 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 syndrome1. 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 study
1 (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 yearsIncidence of symptomaticandrogen deficiency*: 5.6%
MMAS
4
(N=1,691)
Men aged 40–70 years with total testosterone <200 ng/
dL
and ≥
3 clinical features of androgen deficiency
Prevalence:
12.3%
Slide32N=2,162 men aged ≥45 years visiting US primary care practicesHIM, Hypogonadism in Males; TDS, testosterone deficiency syndromeMulligan 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)
Slide33*Tetosterone/SHBG ratio: <0.153 nmol/nmolBLSA, Baltimore Longitudinal Study of Aging; SHBG, sex hormone-binding globulin; TDS, testosterone deficiency syndromeHarman 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
Slide34The daily pattern of male testosterone production is attenuated with age
LH, luteinizing hormoneBremner 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
Slide35SHBG, sex hormone-binding globulinComhaire FH. Eur Urol. 2000;38(6):655–62.
Age-related changes in serum testosterone and SHBG concentrations
Serum concentrations
Age (years)
Slide36SHBG, sex hormone-binding globulinVermeulen A. Ann Med. 1993;25(6):531–4.
Age-related changes in serum testosterone and SHBG concentrations (2)
25
20
1
5
10
5
Serum concentrations
Age (years)
8
7
6
5
Free testosterone
(
nmol
/L)
Total testosterone
(
nmol
/L)
SHBG
(10
-8
mol
/L)
Slide37Clinical signs and symptoms
Module 2: Male hypogonadism
Slide38Dohle 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
Classical symptoms and signsReduced testis volumeMale-factor infertilityDecreased body hairGynecomastiaLoss of vigorDecrease in body mass and muscle strengthObesityMetabolic syndromeInsulin resistance and type 2 diabetes mellitusDecrease in bone mineral density (osteoporosis) with low trauma fracturesMild anemia
Sexual symptoms and signsReduced sexual desire (libido) and activityErectile dysfunctionFewer and diminished nocturnal erections
– Most common symptom/sign in aging men
Cognitive and
psychovegetative
symptoms and signs
Hot flushesChanges in mood, fatigue and angerSleep disturbancesDepressionDiminished cognitive function
Slide39n=521 men with EDED, erectile dysfunctionGuay A et al. J Androl. 2001;22(5):793–7.
Erectile dysfunction is associatedwith male hypogonadism
Patients (%)
Slide40HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol1. 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
testosterone
2
Metabolic and other
Reduction in
HDL-C
and increase in
LDL-C
3
Impaired glucose
metabolism
3
Increase in total body fat (change in
lean:fat
ratio)
3
Osteopenia
Osteoporosis
3
Reduction in red cell volume
Slide41Clinical consequences of hypogonadism are determined by age of onset and severity
Androgen deficiency in uteroAbsence 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 genitaliaLack 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/
Slide42Clinical consequences of hypogonadism are determined by age of onset and severity (2)
Androgen deficiency during pubertyWhen 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/
Symptoms and signs suggesting
prepubertal
-onset
hypogonadism
Delayed puberty
Eunuchoid
habitus
Small testes
Sparse body/facial hair
Cryptorchidism
Infertility
Gynecomastia
Low bone mass
High-pitched voice
Sarcopenia
Unclosed epiphyses
Reduced sexual desire/activity
Linear growth into adulthood
Slide43Clinical consequences of hypogonadism are determined by age of onset and severity (3)
Androgen deficiency during adulthoodWith onset after puberty, the clinical picture of hypogonadism can vary widelyBody proportions, penis size and pitch of voicedo not changeHowever, body and facial hair dwindle and shavingneed not be carried out as frequentlyThe 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/
Slide44Diagnosis
Module 2: Male hypogonadism
Slide45COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; TDS, testosterone deficiency syndromeDohle 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 concentrationsAssessment of TDS should also be considered in men with underlying conditions or who are receiving treatments that are commonly associated with male hypogonadism
Conditions and treatments associated with male hypogonadism
:
Sexual dysfunction
Obesity
Type 2 diabetes mellitus
Metabolic syndrome
Pituitary mass, following radiation involving the
sellar
region and other diseases in the
sellar
and hypothalamic region
Treatment with medications that cause suppression of testosterone levels
e.g.
corticosteroids and opiates
Moderate to severe COPD
Infertility
Osteoporosis or low-trauma fractures
HIV infection with sarcopenia
Slide46AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology; BMI, body mass indexGarvey WT et al. Endocr Pract. 2016;22 Suppl 3:1–203.
Special guidance for overweight orobese men with suspected hypogonadism
AACE/ACE 2016 Clinical Practice Guidelines for Patients with Obesity
All men with increased waist circumference (≥102 cm) or obesity (BMI ≥30 kg/m
2
) should be assessed for hypogonadism by history and physical examination, and
be tested for
testosterone deficiency
All men with hypogonadism should be evaluated for overweight or obesity
All men with type 2 diabetes should be tested to exclude testosterone deficiency
Treatment of hypogonadism in men with increased waist circumference or obesity should include weight-loss therapy
Weight loss of >5–10% is necessary for a significant improvement in serum testosterone concentrations
Bariatric surgery should be considered to improve hypogonadism in most patients with obesity, including those with severe obesity (BMI >50 kg/m
2
) and type 2 diabetes
Men with hypogonadism and obesity who are not seeking fertility should be considered for testosterone therapy in addition to lifestyle intervention
Slide47History-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.
Physical examination should include consideration of:Early morning erectionsPenis sizeGeneral examinations(including blood pressure)Testes (size and consistency according to range in normal adult males) and scrotum e.g. pigmentationSpermatic cord (varicocele)Secondary sexual characteristics – virilization (decreased body hair/beard growth)Body mass indexPubic hair density and distribution patternWaist circumferenceBody proportions e.g. female pattern of fat distribution
History-taking should include consideration of:
Comprehensive history
Patient complaints
Family history
Sexual history
Past or present illnesses
Exposure to drugs, radiation or other toxins
Slide48Clinical assessment of male hypogonadism
The most widely accepted diagnostic parametersfor male hypogonadism are serum total testosterone and free testosterone1–3Clinical 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
.
Slide49Testosterone 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 perception1,2However, 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 therapy1. 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*
Tota
l T<8 nmol/L (231 ng/dL) orFree T<180 pmol/L (5.2 ng/dL)
TDS likelyTTh indicated
Tota
l T8–12 nmol/L (231–346 ng/dL) orFree T180–225 pmol/L (5.2–6.5 ng/dL)
TDS possible, consider TTh(if presence of bothersome symptoms and/or elevated SHBG)
Tota
l
T
>
12
nmol
/L (346
ng/
dL
) or
Free T
>225
pmol
/L (6.5
ng/
dL
)
Slide50Biochemical examination of adult men with suspected hypogonadism
Basic hormonal examinations for male hypogonadism include assessment of testosterone, LH and FSHTestosterone reveals the endocrine activity of the testesLH and FSH are indicators of pituitary function and allow etiological assessment of hypogonadismIncreased gonadotropins indicate primary hypogonadismDecreased gonadotropins in combination with decreased testosterone suggest secondary hypogonadismOther 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.
Slide51Recommendations onmeasuring testosterone levels
Measure total testosterone between 07:00–11:001–4Serum testosterone levels exhibit a circadian variationwith peak values in the morning between 06:00–08:00and a nadir between 18:00–20:002,3Clinical symptoms of hypogonadism may be less clearin older individuals because of blunting of the diurnalvariation of testosterone secretion and otherage-related changes2,3If 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 globulin1. 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/
Slide52Analytical methods formeasuring total testosterone
CLIA, chemiluminescent immunoassay; ELISA, enzyme-linked immunosorbent assay; GC, gas chromatography;LC, liquid chromatography; RIA, radioimmunoassay; T, testosterone1. 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.
Method
Main strengths
Main disadvantages
Direct assay
by RIA, ELISA
or CLIA
1
Technically simple, rapid and inexpensive
High-throughput and fast turnaround time
Can be automated
Often overestimates T concentration
Not standardized (results and reference intervals depend on method)
Limited accuracy at T <300 ng/
dL
Reference intervals in different populations are not well documented
For RIA: generates radioactive waste
RIA after extraction and chromatography
1
Widely used, with well-documented reference intervals in different populations
Large serum volumes can be used, increasing sensitivity
Possibility to assay multiple steroids in the same sample
T released from steroid-binding proteins during extraction
Labor
-intensive, cumbersome,
time-consuming, costly
Requires a high degree of technical expertise
Organic solvents need specialized storage and waste disposal
Imprecise: measurements must be corrected for recovery
Generates radioactive waste
MS after extraction
and LC or GC
1
Gold-standard for measuring total T
2
Multiple steroids can be assayed in the
same sample
Highly accurate when properly validated
Throughput comparable with RIA after extraction and chromatography
Expensive
Standardization is lacking
Limited throughput and long turnaround time
Derivatization steps can introduce error
Organic solvents need specialized storage and waste disposal
Slide53Analytical methods for measuringfree or bioavailable testosterone
RIA, radioimmunoassay; SHBG, sex hormone-binding globulin; T, testosteroneRosner W et al. J Clin Endocrinol Metab. 2007;92(2):405–13; Dean JD et al. J Sex Med. 2015;12(8):1660–86.
Method
Main
s
trengths
Main disadvantages
Direct
RIA
Technically simple, rapid
and inexpensive
High-throughput and fast turnaround time
Can be automated
Poor accuracy, sensitivity and
between-laboratory comparability
Generates radioactive waste
Physical separation of protein-bound T from free T
Accurate
Equilibrium dialysis assay is the
gold-standard for quantifying free T
Good sensitivity and reproducibility
Expensive
Labor
-intensive and technically difficult
Like all indirect measures, highly dependent on accuracy of total T assay
Sensitivity only sufficient for assessment of adult males
Ammonium
sulfate
precipitation to measure bioavailable T
Technically simple
May be inaccurate due to use of impure reagents, incomplete precipitation of globulins and/or between-laboratory differences in methodology
Calculation using algorithms based on law of mass action
Technically simple
Excellent correlation with physical separation measures
Highly dependent on accuracy and sensitivity of total T and SHBG assays
Assumptions and reference intervals
not standardized
Slide54Nebido.com: Online tools for testosterone estimation and calculation
https://www.nebido.com/en/hcp/research/testosterone-tools/
Slide55Questionnaires for hypogonadism screening and outcome measurement
Several patient- and clinician-reported instruments exist for hypogonadism screening and outcome measurementThese questionnaires may assist:Assessment of symptoms prior to starting TThMonitoring of clinical response to TTh during follow-upPatient adherence to TThClinical 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 therapyBhasin 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
Slide56ADAM questionnaire
ADAM, Androgen Deficiency in the Aging MaleMorley JE et al. Metabolism. 2000;49(9):1239–42.
1Do you have a decrease in libido?2Do you have a lack of energy?3Do you have a decrease in strength and/or endurance?4Have you lost height?5Have you noticed a decreased "enjoyment of life"?6Are you sad and/or grumpy?7Are your erections less strong?8Have you noticed a recent deterioration in your ability to play sports?9Are you falling asleep after dinner?10Has there been a recent deterioration in your work performance?
Low testosterone may be suspected if the answer to questions
1
or
7
, or any 3 other questions is ‘
Yes
’
Slide57AMS questionnaire (part 1)
AMS, Aging Male’s Symptoms scalehttp://zeg-berlin.de/expertise/diagnostics-tools/aging-male-symptoms-scale/self-assessment/
Which of the following symptoms apply to you at this time?None1Mild2Moderate3Severe4Extremely severe51Decline in your feeling of general well-being(general state of health, subjective feeling)□□□□□2Joint pain and muscular ache(lower back pain, joint pain, pain in a limb, general backache)□□□□□3Excessive sweating(unexpected/sudden episodes of sweating, hot flushes independent of strain)□□□□□4Sleep problems(difficulty in falling asleep, difficulty in sleeping through, waking up early and feeling tired, poor sleep, sleeplessness)□□□□□5Increased need for sleep, often feeling tired□□□□□6Irritability(feeling aggressive, easily upset about little things, moody)□□□□□7Nervousness(inner tension, restlessness, feeling fidgety)□□□□□8Anxiety(feeling panicky)□□□□□9Physical exhaustion/lacking vitality(general decrease in performance, reduced activity, lacking interest in leisure activities, feeling of getting less done, of achieving less, of having to force onself to undertake activities)□□□□□
Slide58AMS questionnaire (part 2)
AMS, Aging Male’s Symptoms scalehttp://zeg-berlin.de/expertise/diagnostics-tools/aging-male-symptoms-scale/self-assessment/
Which of the following symptoms apply to you at this time?None1Mild2Moderate3Severe4Extremely severe510Decrease in muscular strength(feeling of weakness)□□□□□11Depressive mood(feeling down, sad,on the verge of tears, lack of drive, mood swings, feeling nothing is of any use)□□□□□12Feeling that you have passed your peak□□□□□13Feeling burnt out, having hit rock-bottom□□□□□14Decrease in beard growth□□□□□15Decrease in ability/frequency to perform sexually□□□□□16Decrease in the number of morning erections□□□□□17Decrease in sexual desire/libido(lacking pleasure in sex, lacking desire for sexual intercourse)□□□□□
Total symptom scores correlate as follows with testosterone deficiency symptoms:
17–26
Asymptomatic
27–36
Mild symptoms
37–49
Moderate symptoms
>50
Severe symptoms
Slide59MRI, magnetic resonance imaging; PDE -5, phosphodiesterase type 5; PSA, prostate-specific antigen;SHBG, sex hormone-binding globulin; T, testosterone; TTh, testosterone therapyTraish 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 TProlactin, estradiolThyroid and adrenal axesStimulation test of pituitary glandKaryotype, fertility statusTesticular ultrasoundMRI 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
p
mol/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?
Slide60Associated comorbiditiesand burden of disease
Module 2: Male hypogonadism
Slide61Giannoulis 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 disturbances
on quality of life and detrimental effects on multiple
organ systems, including reduced general well-being, depression, diminished physical strength, and
sexual dysfunction
Slide62Maggio 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
Slide63ADAM, Androgen Deficiency in the Aging Male; CHD, coronary heart disease1. 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 patients1Levels of total and/or bioavailable testosterone are significantly reduced in men with CHD2Approximately 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
Slide64n=831 men with proven CHDCHD, coronary heart disease; T, testosteronePugh 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 (%)
Slide65*p<0.001, **p<0.05 versus healthy controlsCAD, coronary artery disease; SHBG, sex hormone-binding globulinDunajska 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)
**
**
**
*
**
Total
testosterone/
estradiol
ratio
Cardiovascular disease
Slide66*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 intervalHak 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
Slide67CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterolTraish 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:1Androgen deficiency: increased levels of total cholesterol and LDL-C, increased production of pro-inflammatory factors, increased thicknessof the arterial wallAndrogen excess: decreased levels of HDL-CMaintaining androgen levels in the physiological range promotesa favorable lipid profile and has potential benefits for CV health1Restoration of arterial vasoreactivity, reduction in levels oftotal cholesterol, triglycerides and pro-inflammatory cytokines, improvement in endothelial function
Cardiovascular disease
Slide68*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, testosteroneSimon 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 men
with low total T (n=25)
Healthy, adult men
with normal total T (n=25)
*
***
**
**
Cardiovascular disease
Slide69CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterolNational 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 diabetesComponents of metabolic syndrome include:Abdominal obesityDyslipidemiaParticularly hypertriglyceridemia and decreased HDL-C levelsHypertensionRaised fasting plasma glucose levelsInsulin resistance
Metabolic syndrome & diabetes
Slide70International 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
Slide71*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 testInternational 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
Central obesity (defined as waist circumference* with ethnicity specific values)
plus any two of the following four factors:
Raised triglycerides
≥1.7
mmol
/L (150 mg/
dL
)
or specific treatment for this lipid abnormality
Reduced
HDL-C
<1.03
mmol
/L (40 mg/
dL
) in males
<1.29
mmol
/L (50 mg/
dL
) in females
or specific treatment for this lipid abnormality
Raised
blood pressure
Systolic blood pressure
≥130 mmHg
or diastolic blood pressure ≥85 mmHg
or treatment of previously diagnosed hypertension
Raised fasting plasma glucose
≥5.6
mmol
/L (100 mg/
dL
)
or previously diagnosed type 2 diabetes
If >5.6
mmol
/L (100 mg/
dL
), OGTT is strongly recommended,
but is not necessary to define presence of the syndrome
Slide72Traish 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
Slide73*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 intervalLaaksonen 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 (
p
mol
/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
Slide74*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, testosteroneSvartberg 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
Slide75Metabolic 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
Slide76FFA, free fatty acid; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor-1; TNFα, tumor necrosis factor alphaEckel 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
Adipose
tissue
↑ IL-6
↓ Adiponectin
↑ Leptin
↑ TNF
α
↑
Adipsin
(Complement D)
↑ PAI-1
↑ FFA
↑ Insulin
↑ Angiotensinogen
↑ Lipoprotein lipase
↑ Lactate
Inflammation
Type 2
diabetes
Hypertension
Atherogenic
dyslipidemia
Thrombosis
Atherosclerosis
↑Resistin
Metabolic syndrome & diabetes
Slide77IL-6, interleukin-6; LH, luteinizing hormone; TNFα, tumor necrosis factor alphaEckel 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
Adipose
tissue
–
+
–
–
–
+
↑ Triglyceride uptake
↑
Lipoprotein lipase activity
↑
Adipocyte number and size
↓
Testosterone
↑
Insulin resistance
Estradiol
TN
F
α
IL-6
Leptin
Hypothalamic-pituitary axis
↓LH pulse amplitude
Testis
Aromatase
Slide78HbA1c, glycated hemoglobin; SHBG, sex hormone-binding globulin1. 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 diabetes1,2In 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 diabetes2–4Androgen deficiency is associated with metabolic syndrome, insulin resistance, type 2 diabetes and increased deposition of visceral fat2The latter can serve as an endocrine organ, secreting inflammatory cytokines, thus promoting endothelial dysfunction and subsequent development of cardiovascular disease2
Metabolic syndrome & diabetes
Slide79n=355 men with type 2 diabetes (mean age: 58 years)T, testosteroneKapoor D et al. Diabetes Care. 2007;30(4):911–7.
Prevalence of hypogonadism by agein men with type 2 diabetes
Metabolic syndrome & diabetes
Total T <8
nmol
/L
Total T <12
nmol
/L
Patients (%)
Age (years)
>69
<40
Bioavailable T <2.5
nmol
/L
Bioavailable T <4.0
nmol
/L
Calculated free T <0.255
nmol
/L
Age (years)
>69
<40
Slide80CI, confidence interval;MMAS, Massachusetts Male Aging Study; RR, relative risk; SD, standard deviation; SHBG, sex hormone-binding globulin1. 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
Laaksonen
et al. 20042Prospective, population-based cohort studyN=702 middle-aged healthy men(mean age: 51.3 years)Low total T defined as <11 nmol/L(317 ng/dL)Follow-up: 11 yearsOR (95% CI) for incident diabetes2.33 (1.32–4.11) per 1-SD decrease intotal testosterone; p<0.054.34 (2.45–7.70) per 1-SD decrease in SHBG; p<0.05OR (95% CI) for incident metabolic syndrome2.28 (1.54–3.38) per 1-SD decrease intotal testosterone; p<0.052.78 (1.88–4.12) per 1-SD decrease in SHBG; p<0.05
Stellato
et al.
2000
1
Prospective, population-based cohort study
N=1,030 men in the MMAS
(mean age: 53.9 years)
Low total T defined as <8.7
nmol
/L
(250 ng/
dL
)
Follow-up: 9 years
OR (95% CI) for incident diabetes
1.58 (1.08–2.29)
per 1-SD [0.1
nmol
/L
(3.9 ng/
dL
)] decrease in free testosterone;
p=0.017
1.89 (1.14–3.14)
per 1-SD (15.8
nmol
/L) decrease in SHBG;
p=0.014
Slide81Laaksonen et al. 20042
Stellato et al. 20001
Incidence of diabetes
at 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 diabetes
at 11-year follow-up (%)
Patient subgroup
Slide82All-cause prevalence of osteoporosis in men by age2
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 lifetime1Hip fractures contribute to the greatest morbidity and mortality in men1Each 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 fractureMorbidity and mortality associatedwith male hip fractures are greater than those for female hip fractures2Men with known fragility fracturesare less likely to receive treatment than women2
Osteoporosis
Patients (%)
Age (years)
Slide83ADT, androgen deprivation therapy1. 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 osteoporosis1These secondary causes include chronic disease,alcohol abuse, excess glucocorticoids and hypogonadism(both idiopathic and through ADT)2Hypogonadism is responsible for 16–30% of casesof secondary osteoporosis in men1
Osteoporosis
Slide84BMD, bone mineral densityGolds 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 riskTestosterone 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 lossIndirectly, it has inhibitory effects on bone resorption via aromatization to estradiolIt independently maintains muscle strengthand physical performanceThis likely reduces the risk of falls and associated fracture, and contributes to maintenance of BMD and bone health
Osteoporosis
Normal bone
Osteoporosis in a
man
aged 50 years following glucocorticoid therapy
Slide85*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 (%)
*
Slide86CV, cardiovascular; T, testosterone1. 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 expectancy1,2In 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 years1Low testosterone increased mortality risk by 88%1Low testosterone levels are associated with increased risk of all-cause and CV death2
Mortality
Slide87Hypogonadism 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 treatment
n=858 men aged >40 yearsCI, confidence intervalShores MM et al. Arch Intern Med. 2006;166(15):1660–5.
Men with a
n
ormal
testosterone level (n=452)
Men with an e
quivocal
testosterone level (n=240)
Men with a low
testosterone level
(n=166)
Cumulative survival
Survival (years)
Hazard ratio (95% CI)
5
.0
Decreased
risk
Increased
risk
0.5
*
Slide88BPH, benign prostatic hyperplasia; QoL, quality of life; SF-12, 12-Item Short Form Survey; SF-36, 36-Item Short Form Survey1. 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
function
1
In a study comparing 24 men aged >50 years with BPH
treated
with
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
scale
2
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-being
2
Slide89*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 Modification1. 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
Shores
et al.
20052Retrospective, 2-year cohort studyN=748 men without prior ICD-9-CM-diagnosed depressive illness(mean age: 67.1 years)Low T defined as:Total T ≤8.7 nmol/L (250 ng/dL)Adjusted HR** (95% CI) forincident depression2.1 (1.3–3.2); p=0.002Kaplan-Meier survival analysisSignificantly shorter time to depression for hypogonadal versus eugonadal men: log-rank Chi2=8.1, p=0.004
Shores
et al.
2004
1
Retrospective, 2-year cohort study
N=278 men without prior ICD-9-CM-diagnosed depressive illness
(mean age: 62.6 years)
Low T defined as:
Total T
≤6.9
nmol
/L (200 ng/
dL
) or
Free T
≤0.03
nmol
/L (0.9 ng/
dL
)
Adjusted HR* (95% CI) for
incident depression
4.2 (1.5–12.0)
;
p=0.008
Kaplan-Meier survival analysis
Significantly shorter time to depression for
hypogonadal
versus
eugonadal
men:
log-rank Chi
2
=6.9, p=0.008
Slide90Depression
Shores
et al.
20052
Shores et al. 20041
Incidence of depression
at 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 depression
at 2-year follow-up (%)
Patient subgroup
Slide91*p<0.05 versus eugonadal menN=278 men aged ≥45 years visiting US primary care practicesShores 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
Slide921. 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:
Diabetes3In 2012, direct medical costs for diabetes were estimated at $306 billion, or >20% of all medical care costs in the USAPatients with diabetes havea 2.3-fold greater annual medical expenditure than those without diabetes,and incur $69 billion in costs related to absenteeism, reduced productivity, diabetes-related disabilityand premature mortality
Obesity
Obesity has been shown to impair health-related quality of life, and this is exacerbated by grade of obesity, and comorbid type 2 diabetes, metabolic syndrome and/or chronic inflammation
1
Men report that obesity is associated with a negative impact on biopsychosocial functioning, which is closely related to poor physical health and body image
2
Slide93ED, erectile dysfunction; PDE-5, phosphodiesterase type 5; TDS, testosterone deficiency syndromeMaggi 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:
DepressionDepression is the most costly brain disorder in Europe; in 2004, the total annual cost was ~€118 billionFor each person with depression, annual direct costs of care are ~€2,000 and indirect costs due to morbidity/mortality are ~€3,500
Osteoporosis
In a 1999 French study, the estimated mean cost per related fracture was ~€8,500Absenteeism from work and school for patients and informal carersis common
Sexual dysfunction
In a 1998 UK study, estimated annual healthcare costs per patient were ~£160 (€253) Costs are even higher for diabetic patients with ED, in whom first-line treatment with PDE-5 inhibitors has failed due to undetected TDS
Slide94Summary
The majority of international societies have defined
male 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 in
the
testis
(
primary
), hypothalamus/pituitary
gland (
secondary
) or both (
mixed
/
adult-onset
/
functional
),
as
well as target or
gan androgen insensitivity/resistance and disease or toxins
S
ubclinical hypogonadism associated with aging (
compensated hypogonadism
)
is also recognized as a distinct clinical entity
Slide95Summary (2)
The prevalence/incidence of male hypogonadism is high and increases with ageMale hypogonadism is associated with a variety of symptoms and signsThe 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 statusObesity is the single most-powerful predictor of low testosteroneA diagnosis of male hypogonadism comprises persistent clinical symptoms plus biochemical evidence of consistently low serum testosterone concentrationsAssessment 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
Slide96Summary (3)
Male
hypogonadism
commonly occurs w
ith 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