LOW TESTOSTERONE: WHEN, HOW & WHAT TO DO?

LOW TESTOSTERONE: WHEN, HOW & WHAT TO DO?

Premal Patel, MDAssistant Professor

Male Infertility, Microsurgery & Sexual MedicineUniversity of Manitoba

www.manitobafertility.com

Faculty/Presenter Disclosure

• Faculty: Premal Patel, MD FRCSC

• Relationships with financial sponsors:– Speakers Bureau/Honoraria: Aytu Biosciences, Boston Scientific

– Consulting Fees: Nestle Health, Boston Scientific


Disclosure of Financial Support

• No financial disclosures to report

• Potential for conflict(s) of interest:• No Potential Conflict of Interests


• No relevant conflict of interest for this talk

Mitigating Potential Bias


Overview

• Understand the physiology and etiology of testosterone deficiency

• When and how to treat testosterone deficiency

• How to monitor patients on testosterone replacement therapy


Production and Regulationof Testosterone

40% of serum testosterone is “bioavailable”

Free T2%

SHBG-bound T 60%

Albumin-bound T

38%

GnRH

LH FSHTestosterone

Testosterone

Sperm

Hypothalamus

Pituitary

Testis


Prevalence of Low Testosterone:13.8 Million Men in the US

Overall, 38.7% of men >45y

have T-levels < 10.4 nmol/L

Pre

vale

nce

of

Low

T in

All

Enro

lled

P

atie

nts

(%

, 95

% C

I)

0

10

20

30

40

50

60

>85

Patient Age Range

45 to

54

55 to

64

65 to

74

75 to

84


74

5250 50

4240

19

0

10

20

30

40

50

60

70

80

90

100

(%)

Prevalence of Low Testosterone in Other Conditions

Ob

esit

y

Dia

bet

es

Hyp

ert

ensi

on

Dys

lipid

emia

Ch

ron

ic O

pio

id U

se

AID

S

ED


Hypogonadism in the Aging Man

• All components of testosterone decline with normal aging

• Decline in Leydig cell count and function

• Increase SHBG, lowers bioavailable T

• Not all men with low testosterone have symptoms or need treatment


Age-Related Changes in Testosterone

Test

ost

ero

ne

(nm

ol/

L)

Age (Years)

10

12

14

16

18

20

30 40 50 60 70 80 90

(177)

(144)(151)

(158)

(109)

(43)


Male Hormonal StatusChanges with Age as SHBG Increases

FTn

mo

l/L

0

10

20

30

40

50

60

70

80

<34 35-44 45-54 55-64 65-74 >75

Age (y)

Testosterone SHBG


Aging Males and MortalityMen with Low T May Not Live As Long

• 800 Men, 50-91 y, followed for 18 y

• 1/3 had low T

• Men with low T versus those with higher T had:

Increased levels of inflamm-

atorycytokines

Increased waist girth

3x more likely to

have metabolic syndrome

40% greater risk of death


Aging Males and MortalityLow Serum T and Mortality in Male Veterans

Survival (y)

1.0

0.5

0.9

0.8

0.7

0.6

0 2 4 6 8 10

Cu

mu

lati

ve S

urv

ival

Men With a Low T-Level (n = 166)

Men With a Normal T-Level (n = 452)

T-Level Mortality (%)

Normal 20.1

Low 34.9


The Impact of TestosteroneSkin

Hair growth, balding, sebum production

LiverSynthesis of serum

proteins

Male Sexual OrgansPenile growth,

spermatogenesis, prostate growth, and function

BrainLibido, mood

MuscleIncrease in strength and volume

KidneyStimulation of erythropoietin production

Bone MarrowStimulation of stem cells

BoneAccelerated linear growth,

closure of epiphyses

Guyton AC. In: Textbook of Medical Physiology. 8th ed. 1991:891-895.www.manitobafertility.com

Potential Effects of Hypogonadism

Long-term complications• Decline in libido and erectile function

• Increased body fat mass

• Decreased muscle mass, bone mass, and strength

• Possibly: fatigue, mood / cognitive changes

• Increased incidence of osteoporosis


Testosterone and Sex

• ED exclusively related to hypogonadism is rare (5%)

• In hypogonadal men with ED, return to low level of normal testosterone range is adequate

• Libido is most likely to improve with treatment

• Spermatogenesis is greatly reduced with testosterone replacement, and may not be reversible with cessation (5% of men)


It doesn’t take much for a man with testosterone to

become aroused



Diagnosis of Low Testosterone:

• Symptoms• Signs• Decreased T


What Is Considered a Low Serum T-Level?

1*

Should I be going by reference ranges?


What Is Considered a Low Serum T-Level?

• American Urological Association & Endocrine Society• Low Testosterone: < 10.4 nmol/L (300 ng/dL)


Diagnostic Testosterone Testing: Initial Tests

• Serum Total Testosterone (free plus protein-bound)

Morning sample recommended in young men

• Serum Bioavailable T (free plus albumin-bound)

Measures albumin-bound and free testosterone

Best test, most expensive.


Diagnostic Testosterone Testing: Additional Tests

• LH and FSH

• Serum Prolactin (TT < 5.2 nmol/L + low LH/FSH or signs/symptoms)

• Baseline PSA (in men > 50y or family history of Prostate Cancer)

• Baseline Hematocrit


Confirmed low T (Total < 10.4 nmol/L)

OR

Free or Bio T < normal (Free T <179 pmol/L)

Low T

Low or normal LH+FSH

Prolactin, iron sats

Other pituitary hormones

Low T

High LH+FSH

Karyotype

Klinefelter Syndrome

Other Testicular Insult

Secondary Hypogonadism Primary Hypogonadism

MRI in

certain cases


Key Symptoms and Signs Associated with Low Testosterone

Symptoms• Increased body fat,

BMI

• Reduced muscle bulk and strength

• Low BMD

• Loss of body hair (axillary and pubic), reduced shaving

Signs• Decreased energy

or motivation • Depressed mood• Diminished libido,

ED• Diminished work

performance• Poor concentration

and memory• Sleep disturbance



Testosterone Replacement Therapy:

Treatment Options


Contraindications to Testosterone Therapy

• Breast or metastatic prostate cancer

• Cardiovascular disease (recent MI, angina or CHF; 3-6 months)

• Lump/hardness on prostate exam by DRE

• PSA >3 ng/ml that has not been evaluated for prostate cancer

• Severe untreated BPH (AUA/IPSS >19)

• Erythrocytosis (hematocrit >50%)

• Untreated obstructive sleep apnea


Risks of Testosterone Replacement Therapy (TRT)

• Hepatic adverse effects with oral therapy

• Polycythemia

• Edema

• Gynecomastia

• Precipitation or worsening of sleep apnea

• Infertility


Risks of Testosterone Replacement Therapy (TRT)

• Cardiovascular Disease?

• Prostate Cancer?


100100 200200 300300 400400 800800500500 600600 70070000

Serum testosterone level (Serum testosterone level (ng/dLng/dL))

Pro

stat

e G

row

th (

PS

A)

Pro

stat

e G

row

th (

PS

A)

Saturation EffectSaturation Effect

Unsatu

rated

Unsatu

rated

““Normal Physiologic Range”Normal Physiologic Range”

Virtually Virtually

CastrateCastrate

SaturationSaturation Model of Physiologic Testosterone ReplacementModel of Physiologic Testosterone Replacement

120-150 ng/ml

= PSA

1*www.manitobafertility.com

TRT Treatment Options

Oral Tablets

Intramuscular

Injections

Transdermal

Gels

Transdermal

Patches


How Do You Give Testosterone?

• Start at standard dose

• Check levels

• Therapeutic target• Serum testosterone in mid-normal range for healthy, young

men (14 – 17.5 nmol/L)

• Target in older men• Considerable disagreement among experts

• Aim for low-mid range (14 – 17.5 nmol/L)


Non-genital Transdermal Patch

• Mimics normal diurnal rhythm

• Less increase in hematocrit than IM shots

• Start at 1-2 x 5 mg nightly to the skin of the back, thigh, or upper arm• Away from pressure areas

• Some men need 2 patches

• Skin irritation/redness/rashes


Testosterone Gel

• Starting dose 5-10 grams daily

• Skin tolerates it well

• Potential transfer to others by skin contact• Cover the application site

• Wash hands with soap and water after application

• Wash skin before skin-to-skin contact with others

• T levels maintained when skin washed 4-6 hours after application


Testosterone Enanthate or Cypionate Injections (IM)

• T levels are supraphysiologic, then gradually drop to hypogonadal range

• Peaks and valleys

• Fluctuation of mood or libido

• Relatively inexpensive if self-administered

• Start at 75-100 mg IM weekly

• Or 150-200 mg IM every other week

• Pain at injection site

• Excessive erythrocytosis (esp in older pts)


Monitoring T Levels

• Target the mid-normal range

• Timing• Patch: 3-12 hours after application

• Gel: after 1-2 weeks of treatment

• Injections: 6 weeks after treatment, q 3months for 1st year, q 6months after


Safety Monitoring

• Baseline• Testosterone level, DRE, PSA, Hematocrit

• Follow-up ~3 months then annually• Assess improvement/side effects

• Testosterone, Estradiol, Hematocrit, DRE

• PSA• age- and race-appropriate interval

• If osteoporosis – DXA at 1-2 years


Testosterone for the Following Reasons May be Harmful

• To improve strength/athletic performance

• For physical appearance

• To prevent aging


Management of adverse effects

• Erythrocytosis: • HCt > 53% - phlebotomy q 2 weeks +/- adjust

testosterone dosage

• Elevated serum estradiol • E > 60 pg/mL – anastrozole 1mg BIW

• Acne – minocycline

• Gynecomastia (with normal E) – tamoxifen 20mg BID


Conclusions

• Low T in adult men is often underdiagnosed and undertreated

• T levels gradually diminish with age, often to hypogonadal levels (<10.4 nmol/L)

• TRT has several alternatives – gels, injections & patch

• TRT is safe with proper monitoring (PSA, HCt, estradiol)

• CaP and CV risks need to be discussed prior to TRT


1. Adapted from Braunstein G.D.. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433.2. Mulligan T, et al. J Clin Pract, 60(7):762-769, 2006.3. Bodie J, et al. J Urol, 169:2262–2264, 2003.4. Daniell HW, J Pain, 3:377-384, 2002.5. Dobs AS, Clin Endocrinol Metab, 12:379-370, 1998.6. Grinspoon S, et al. Ann Intern Med, 129:18-26, 1998.7. Mulligan T, et al. Int J Clin Pract, 60:762–769, 2006.8. Tenover J.L. Endocrinol Metab Clin North Am. 1998;27:969-987.9. Swerdoff, R.S. Summary of the Consensus Session from the 1st Annual 10. Andropause Consensus Meeting. The Endocrine Society, April 2000.11. Adapted from Harman S.M., et al. J Clin Endocrinol Metab. 2001;86:724-731.12. Gray A, et al. J Clin Endocrinol Metab, 73:1016-1025, 1991.13. Kupelian V, et al. Clin Endocrin Metab, 91:843-850, 2006.14. Laaksonen DE, et al. Diabetes Care, 27(5):1036–1041, 2004.15. Laughlin G, et al. ENDO, Abstract OR55-2, 2007.16. Shores M, et al. Arch Intern Med, 166:1660-1665, 2006.17. Tenover J.L.. Endocrinol Metab Clin North Am. 1998;27:969-987.18. Bhasis, S., Mayo Clin Proc 2000; 75: S70.19. Leungwattanakij, S., et al, Mediguide to Urology, 2000; 13:1.20. Tenover J.L.. Endocrinol Metab Clin North Am. 1998;27:969-987.21. Petak S.M., et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html.22. AACE Hypogonadism Task Force. Endocrinol Pract, 12:193-222, 2006.23. Bhasin S, et al. Testosterone Therapy for Hypogonadism Guideline. J Clin Endocrinol Metab, March 2018.24. Morales A, et al. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guidement. CMAJ December 08, 201525. Tenover J.L.. Endocrinol Metab Clin North Am. 1998;27:969-987.26. Braunstein G.D.. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403.27. Morgentaler A, Traish AM. Eur Urol. 2008;55:310-32028. Mulhall JP et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018 Aug;200(2):423-432.

References


http://www.aace.com/clin/guidelines/hypogonadism.html

Questions?

@PremalPatelMD

[email protected]

For consults (Fax): 204-787-3040- Male Infertility

- Testosterone Deficiency

- Erectile Dysfunction

- Male Incontinence

- BPH

- Peyronie’s Disease


mailto:[email protected]

Documents

LOW TESTOSTERONE: WHEN, HOW & WHAT TO DO?