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Prof Gary WittertFreemasons Foundation Centre for Men’s Health

Research and Discipline of Medicine, University of Adelaide

South Australian Health and Medical Research Institute

Low Testosterone in Men: What does it mean and how should it be managed?

GP Education Day Health Ed

17 September 2016

Conflicts of Interest

Research funding• Bayer Schering

• Eli Lilly

• Lawley Pharmaceuticals

Speaking Fees• Bayer Schering

• Eli Lilly

• Bhesins Pharmaceuticals

Advisory Board

• Eli Lilly

•Physiology of Testosterone and the HPG axis

•Measurement of plasma testosterone

• Ageing, obesity and testosterone

•Testosterone deficiencyCausesConsequencesApproach to diagnosis

•Testosterone replacement therapy

When it is indicated and when is it not?Cardiovascular and prostate safetyMonitoring and precautions

Outline The Hypothalamo-Pituitary Gonadal AxisIntegration of environmental, and metabolic cues

within the hypothalamus

Donato J & Elias CF. Front. Endocrinol., 2011

Axelsson J et al. JCEM 2005;90:4530-4535

Day sleep vs. night sleep conditions educed by “lights out“

Lights out Wake

The circadian increase in T is related to sleep irrespective

of timing (young men)

T does not increase when sleep is totally

fragmented

Healthy young men n=16

Luboshitzky et al J Clin Endocrin Metab 86(3):1134-1139, 2001.

Factors increasing and decreasing SHBG

• Anabolic steroids

• Acromegaly

• Excess Monosaccharide intake

• Glucocorticoids/progestins

• Hypothyroidism

• Low protein (nephrotic)

• Obesity with insulin resistance

SHBG

Total T

SHBG

• Estrogens

• Alcohol

• Anticonvulsants

• Hyperthyroidism

• Hepatitis, cirrhosis

• Nutritional deprivation

SHBG

Total T

Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006

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Measurement of Testosterone

Relationship of T measures to phenotypic endpoints by ageand obesity.

GE – greater than or equal to

LT –less than

Correlations of T measures with phenotypic endpoints vary by age and obesity• CI and LCMS perform similarly • cFT - lowest correlation; not

more informative in aging and obesity

Plotting symbols presented for correlations significant at p<.05

Serum T in older men self-reporting very good health

Sartorius G et al Clinical Endocrinology 2012

Smoothed centile plots of circulating T and SHBG across the lifespan in males

Plotted for each year of age at centiles 2.5%, 25%, 50% (median), 75% and 97.5%.

• Single laboratory and testosterone immunoassay• Smoothed centiles by GAMLSS modelling• N = 58,374

Handelsman DJ, Sikaris K, Ly LP. Ann Clin Biochem. 2015.

Non-significant annualized T change of -0.13nmol/L/y (95% CI: -0.62, 0.41) or an approximate decline of 0.80%/y )

Baseline Follow-up

-10

12

34

lgtt_m1 lgtt_m2

Ageing not independently associated with decreased T

Shi, Wittert et al J Clin Endocrinol Metab 2013

Age and the 5-year Annualised Change in Testosterone

Cohort divided into two groups: •Healthy at wave one and two (no reported or identified abnormality by self-report, clinical exam, on labs, or by data linkage)•Unhealthy at either waveModel adjusted for smoking, alcohol, exercise, and numbers of medications.

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Change in obesity status is the primary determinant of change in testosterone with ageing

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

Normal to obese Obese to normal

Shi, Wittert et al J Clin Endocrinol Metab 2013

Testosterone increases with weight loss

Grossmann, JCEM 96:2341, 2011

Other Factors Affecting Testosterone

• Pharmacotherapy– Opioids

– Statins

• Depression

• Life-course events and psychosocial factors– Death of a spouse

– Social defeat

– Fatherhood

• Smoking

• Alcohol – binge drinking and chronic heavy intake

• Severe sleep and circadian rhythm disruption

• Level of sexual activity

Statins lower serum T in men: Results of a meta-analysis

Schooling MC et al BMC Med. 2013; 11: 57.

P=0.0005 P=0.12 P=0.87 P=0.95

Effect of OSA on Testosterone

P<0.0001 P=0.0003 P=0.32 P=0.26

P=0.01 P=0.09 P=0.08 P=0.78

Psychobiological profiles (e.g. a male with low T) emerge through variable psychosomatic and psychosocial pathways. Interaction between those profiles & depression influenced by social (e.g. partnering & parenting status; SE gradients), cultural (e.g. gender and family life domains), and ecological (e.g. the lived environment, particularly related to low SES and poverty) contexts.

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Depression and Testosterone

Hypogonadism – an amotivational state and some flattening of affect improved with T treatment

Effect of depression on T is not entirely clear

Despite some conflicting studies T does not improve depression

Pathological HypogonadismVs Functional or

Pseudohypogonadism

Primary Hypogonadism

T

LH / FSH

GnRH

T

Inhibin BDHT

T

Sperm

E2

• Klinefelter syndrome

• Myotonic dystrophy

• Developmental disorders

• Orchitis

• Irradiation

• Castration, trauma

• Drugs (cytotoxic, ketoconazole, spironolactone)

Secondary Hypogonadism

T

Normal- LH / FSH

GnRH

T

Inhibin BDHT

T

Sperm

E2

Pathological Causes

• Kallmann syndrome, Prader Willi and other complex genetic disorders

• Hemochromatosis

• Hyperprolactinemia

• Hypopituitarism (tumor, infiltration, destruction)

Functional Causes (Pseudohypogonadism)

• Opiates

• Glucocorticoids, GnRH-A

• Acute and chronic illness*, wasting

• Nutritional deficiency,

• Obesity

• Requires compatible clinical features

• Unequivocally low testosterone level

• Absence of functional remediable cause

Diagnosis of Hypogonadism Requiring Testosterone Treatment

Clinical Features of Hypogonadism

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Age Effects

1st trimester Incomplete virilization

3rd trimester Micropenis

Pre-puberty •Incomplete puberty

•Eunichoidal body habitus*

Post-puberty •Decreased libido, energy, motivation

•Decreased pubic hair, muscle mass and strength, bone mass, red cell mass,

•increased body fat.

•Hot flushes, sweats, fatigue, flat mood, lack of motivation, sleep disturbance, Changes in skin

*Arm span 2 cm longer than vertical height; lower body segment 2 cm longer than upper body segment

Effects of Androgen Deficiency in Relation to Life Stage

Establishing an Endocrine Diagnosis of Hypogonadism

Day-to-Day Variation in T Levels

• Initial T 11 mmol/L - 30% normal T on repeat testing

• Initial T 8 mmol/L– 20% had average T > 11 mmol/L over 6 months

– If average of two T tests ≤ 8 mmol/L none had average T > 11 mmol/L over 6 months.

1Swerdloff RS, et al, J Clin Endocrinol Metab 85:4500-4510, 20002Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007

Use and interpretation of serum T assays

• Measure only if clinically indicated

• Use Total Testosterone

• Affected by food – measure fasting.

• Circadian Variation – measure soon after waking

• Measure on at least 2 occasions

• Consider the SHBG

• Illness, drugs, nutritional deficiency, stress, depression, sleep disorders transiently low T

• Heavy alcohol consumption can decrease serum T

• Smokers have T levels 5-15% higher than nonsmokers.

Biochemistry•LH, FSH, prolactin, thyroid function,

•glucose, lipids

Other as indicated• Karyotype

• Iron studies

• MRI pituitary

Investigations to Determine Cause

Nothing beats a carefully taken history and physical examination including height, weight, waist circumference

Potential consequences of low testosterone

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Testosterone is an Independent Risk Factor for Progression to T2DM

Endocrine Society 2011 P1−339

Low T Predicts Development of T2DM among Men at High but Not Low Metabolic Risk

Massachusetts Male Ageing Study Endocrine Society 2011 P1

Data from 3 recent cohort studies shows that high serum SHBG, but not sex steroid levels are associated with increased facture risk

Cawthon PM et al Bone. 2016 Mar;84:271-8.Hsu et al J Bone Miner Res. 2016 Jul 1

Vandenput L et al J Bone Miner Res. 2016 Mar;31(3):683-

Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton.

Finkelstein JS et al J Clin Invest. 2016 Mar 1;126(3):1114-25.

Bone Mineral Density and Fracture Low Testosterone and CV Mortality

Araujo &Wittert J Clin Endo Metab 2011

Low Testosterone and All-Cause Mortality

Testosterone treatment – Benefits and Risks

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Cunningham GR et al. The Journal of Clinical Endocrinology & Metabolism 2016, 101, 3096-3104.

*

*

* NS

Effects of T Administration for 3 Years on Sexual Function in Older Men With Low or Low-Normal T

N = 308Age 60+T 100-400

Basaria S et al JAMA. 2015;314(6):570-581.

n Age BMI AMS Base

Duration wka

TT Base

TT Treat

AMS Treat Effect on Sexual Function

Hackett et al

199 62 33 41 30 9.2 11.2 No changeb

IIEF EF +2.8 (95% CI 0.8, 4.8) Intercourse satis, +1.3 (95% CI 0.3, 2.4) SD +0.9 (95% CI 0.4, 1.5) Orgasm, +1.4 (95% CI 0.4, 2.3)Overall satisfaction +0.4 (95% CI −0.3, 1.1)

Jones et al

220c 60 32 40 26 9.4 19.5 No change

Improve in IIEF SD (P < .01) No improvement:• EF• Intercourse satisfy• Orgasm, or overall satisfaction

Giltayet al

184d 52 35 43 30 7.7 12.9Improve −7.4 (95% CI −4.3,

−10.5)IIEF-5 +3.1 (95% CI 1.8, 4.4)

Randomized Controlled Trials of T Therapy on Symptoms in Men With T2D and low T

aDouble-blind phase.bAMS improved (P = .02) in men without depression at baseline.cMen had either diabetes (n = 137) and/or the metabolic syndrome.dParticipants had a diagnosis of the metabolic syndrome, 56 of whom also had type 2 diabetes.

Gianatti et al JCEM 2014

Changcheng G, et al Exp Ther Med. 2016 Mar; 11(3): 853–863.

Effect of T treatment on Bone Mineral Density in Hypogonadal Men

Hoyos CM et al. Clin Endocrinol 2012;77(4):599-607.

• Testosterone (T) increased ODI and SpO2T90% at wk 7 but not wk 18

• No effect on any sleep or breathing variable; Subjective sleepiness improved the same in both groups; No discontinuations because of any sleep-related problem

Effect of T on Sleep Disordered Breathing (SDB) and Sleep

Mean difference (with 95%CI) in HbA1c across randomized controlled trials between testosterone- and placebo-treated groups.

Effects of testosterone on glucose metabolism in men with T2DM

Grossmann et al Clin Endocrinol (Oxf). 2014

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Testosterone Treatment and CVD Outcomes

Clinical Trials• T in frail men age 65+ years & low T stopped due to treatment related CV events

• Similar study with less frail men and lower T exposure no increased CV events

Observational studies based on health care data bases • VA system - 8000 men; coronary angiography ; low T.

• T increased CV events after adjustment for 50 variables.

• Unable to quantitate actual exposure to T beyond single prescription.

• Increased CV events but neither the baseline T level nor the use of T beyond a single issue prescription were known.

• VA system T treatment decreased the risk of death irrespective of age, presence of diabetes, or coronary heart disease

Effects of T for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal T

Basaria S et al JAMA. 2015;314(6):570-581.

N = 308Age 60+T 100-400

Testosterone and the Prostate

• No increase in risk of prostate cancer

• Risk of obstruction only an issue in presence of severe voiding symptoms

Raised Haematocrit

• Dose related

• More marked if there is a pre-existing drive to heamatopoeisis

• Reduce dose or dose interval

• Venesect

Contraindications to Testosterone Therapy

• Very high risk of adverse outcomes– Prostate cancer

– Breast cancer

• High risk of adverse outcomes– Undiagnosed prostate nodule

– Unexplained PSA elevation

– BPH with severe obstructive (voiding) symptoms

– Erythrocytosis

– NYHA Class III or IV heart failure

– Unstable IHD

– Recent CVA, TIA.

– Thrombophilia

Conclusion• Ageing per se has a minimal and almost certainly clinically insignificant effect on

serum T.

• The apparent effect of ageing is due to other factors - obesity & associated cardio-metabolic disease, smoking cessation, medication use, alcohol.

• Low T is an independent factor for

– incident T2DM in at risk men (older, more obese)

– Incident CVD

– Overall mortality

• Weight loss, treatment of underlying disease and attention to lifestyle factors.

• The benefits and risks of T beyond clearly defined pathological hypogonadism remains to be determined.

• For patients on opioids or glucocorticoids T may be indicated on a case by case basis if drug cannot be stopped.

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NH&MRC Project Grant (Application ID: APP1030123). Australian New Zealand Clinical Trial Registry number:

ACTRN12612000287831

www.T4DM.org.au

Acknowledgements

Freemasons Foundation Centre for Men’s HealthSean MartinAndrew VincentEvan AtlantisGeorge HatzinikolasMatthew Haren (UniSA)Peter 'O'LoughlinLeanne OwenJoule LiJason Tan

NH&MRC Centre for Nutritional PhysiologyKylie Lange

Population Research Outcome Studies CentreAnne TaylorJanet GrantSandy PickeringZumin Shi

New England Research Institutes MA John McKinlayAndre Araujo

FundingNational Health and Medical Research CouncilFreemasons Foundation, Premiers Science Research Fund, South Australia Department of Health, Florey Foundation, Resmed, Northern Community Health Foundation. Bequest of Geoffrey Ernest Stolz

Health ObservatoryRobert AdamsSarah AppletonJoule Li

Adelaide Institute for Sleep Health.Andrew Vakulin

T4 DM Team

TQEHDavid JesudasonJim WangJason Tan