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Testosterone Replacement in

Adults

John A. Seibel, MD, MACE

History of Testosterone Rx

• Ancient Europe and Asia

– Castrated males had no secondary sex charistics

– Used as eunichs to guard Women

• 1765 Hunter Transplanted Tissue in Animals

• 1849 Berthold “Results of Castration Caused

by a substance secreted from testicles.

Dr. Brown-Sequard

Auto Injected Extract

• “…a radical change took place in me….I fully

regained my old powers….My limbs…showed

a decided gain of strength. With regard to

the facility of intellectual labour,…a return to

my previous ordinary condition became quite

manifest during and after the first two or

three days of my experiments.”

• Called Testosterone “the Elixir of Life”.

Brown-Sequard 1889

• Immediately 12,000 Physicians began injecting

“testosterone extract”

• Unfortunately it had little testosterone and

the effects were placebo.

Sergio Veronoff 1920

• Began transplanting animal testes into men.

• Others used goat and sheep testicles.

• Uniformly rejected by the body and the only

effects were placebo

Synthetic Testosterone

• 1935 David isolated testosterone

• 1939 Kock used Used 40 pounds of bull testes to

get 20 mg of testosterone

• 1939 Butenandt and Ruzika received Nobel Prize

in Medicine for synthesizing Testosterone

• Testosterone injections began

• 1990 patch is introduced.

Role of Testosterone in

Male Health

The Impact of Testosterone

Hair growth, balding,

sebum production

Synthesis of serum

proteins

Male Sexual Organs

Penile growth,

spermatogenesis, prostate

growth, and function

Libido, mood

Muscle

Increase in

strength and

volume

Kidney

Stimulation of

erythropoietin

production

Bone Marrow

Stimulation of

stem cellsBone

Accelerated linear

growth, closure of

epiphyses

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

TESTOSTERONE SECRETION

Testosterone Production

Adapted from Bagatell CJ, Bremner WJ. N Engl J Med. 1996;334:707-714.

LH FSHTestosterone

Testosterone

Hypothalamus

Pituitary

Testis

Production and Regulation of Testosterone

Hypothalamus

Pituitary

Testes

Leydig cells

FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone;

LH = luteinizing hormone; T = testosterone.

Costanzo LS. Physiology. 3rd ed. Saunders Elsevier; 2006:449.

Sertoli cells

Definition of Male Hypogonadism

“ … clinical syndrome that results from failure of the testes to produce

physiological levels of testosterone … due to disruption of one or more levels

of the hypothalamic-pituitary-gonadal (HPG) axis.”

Endocrine Society Guideline (2006)

“ … inadequate gonadal function, as manifested by deficiencies in …the

secretion of gonadal hormones.”

American Association of Clinical Endocrinologists Guidelines (2002)

Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):1995-2010.

Petak SM, et al. Endocr Pract. 2002;8(6):440-456.

Definition of Hypogonadism

• Male gonadal dysfunction

• Low levels of testosterone

• May be congenital or acquired

Winters SJ. Arch Fam Med. 1999;8:257-263; Petak SM, et al. AACE Clinical Practice Guidelines.

Available at: http://www.aace.com/clin/guidelines/hypogonadism.pdf. Accessed October 16,

Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.

Signs And Symptoms of Low T

• Loss of muscle mass and strength• Loss of libido and erectile function• Depression• Fatigue• Osteoporosis• Hot Flashes, Sweats

• Some regression of secondary sexual

characteristics• Oligospermia or azoospermia

• Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.

• Petak SM, et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/jypogonadism.pdf•

Incidence of Hypogonadism

Prevalence of Low Testosterone

13.8 Million Men in the US

40.2% 39.9%

45.5%50%

45 to 54 55 to 64 65 to 74 75 to 84 85+ Total

Patient Age Range

Overall, 38.7% of men ≥≥≥≥45 years had

testosterone levels <300 ng/dL

Mulligan T, et al. Int J Clin Pract. 2006;60(7):762-769..

Patients recruited for study from 2003-2004.

Prevalence and Treatment of

Hypogonadism

10-14 Million Men with Hypogonadism

Adapted from US Food and Drug Administration Updates. Skin patch replaces

testosterone.

Available at: http://www.fda.gov/fdac/departs/196_upd.html. Accessed May 23, 2003.

10%of men arecurrently treated

Low Testosterone Is Increasingly

Common as Men Age

• Men in their 40s and 50s1 in 10

• Men in their 60s1 in 5

• Men in their 70s1 in 4

However, less than 10% are being

treated for low testosterone

Available at: http://www.fda.gov/fdac/departs/196_upd.html Accessed March 20, 2009.

Conditions

Associated with

Hypogonadism

Prevalence of Low Testosterone in

Other Conditions

ED = erectile dysfunction

1. Daniell HW. J Pain. 2002;3:377-384; 2. Mulligan T, et al. Int J Clin Pract. 2006;60:762-769; 3. Grinspoon S, et al. Ann Intern

Med. 1998;129:18-26; 4. Dobs AS. Baillière’s Clin Endocrinol Metab. 1998;12:379-390; 5. Bodie J, et al.

J Urol. 2003;169:2262–2264.

Chronic Opioid Use

• Direct Effect on Hypothalamus

– Decreases GhRH Production & Release

• Direct Effect on Testes

– Decreases Production of Testosterone and

Androgenic Binding Proteins

• Effect begins almost immediately

Prevalence of Low Testosterone in

HIV and AIDS• 30% of men with HIV and

50% of men with AIDS are

hypogonadal1,2

• Mechanisms of

hypogonadism in men with

HIV and AIDS are complex

and not fully understood2

1Grinspoon SK, et al. N Engl J Med. 1992;327-1360-1365; 2Dobs AS, et al. J Clin Endocrinol Metab. 1996;81:4108-4112.

Acquired Causes or Conditions

• Pituitary adenoma

• Inflammatory diseases (rheumatoid arthritis, Crohn’s disease,

ulcerative colitis)

• Respiratory disorders (asthma, COPD, sleep apnea)

• Iatrogenic (ketoconazole, glucocorticoids, spironolactone, cimetidine,

phenytoin, flutamide, opioids)

• Other endocrine disorders (hyperprolactinemia, hypothyroidism)

• Alcohol or anabolic steroid abuseWinters SJ. Arch Fam Med. 1999;8:257-263; Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987; Gordon GG, et al. J Clin Endocrinol Metab. 1975;40:1018-1026; Doerr P, Pirke KM. J Clin Endocrinol Metab. 1976;43:622-629; Tengstrand B, Carlstrom K, Hafstrom I. Rheumatology (Oxford). 2002;41:285-289.

Primary Hypogonadism (Primary Testicular Disorder):

Acquired Causes

• Medications

• Obesity

• Severe systemic illness

• Castration

• Hemochromatosis

• Mumps orchitis

• Idiopathic

• Neurodegenerative

illnesses

• Malnutrition

• Respiratory disorders

• Trauma

Winters SJ. Arch Fam Med. 1999;8:257-263.Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.Gordon GG. J Clin Endocrinol Metab. 1975;40:1018-1026.Doerr P, Pirke KM. J Clin Endocrinol Metab. 1976;43:622-629.Tengstrand B, Carlstrom K, Hafstrom I. Rheumatology (Oxford). 2002;41:285-289.

Diabetes/Metabolic Syndrome

and Low Testosterone Levels• Men with metabolic syndrome or type 2 diabetes may

have concurrent low testosterone

• In three major studies with >2800 patients, patients with metabolic syndrome or type 2 diabetes were more likely to be in the lowest testosterone quartile1-3

– Laaksonen et al. Diabetes Care. 2004; Kupelian et al. J Clin Endocrinol Metab. 2006; Muller et al. J Clin Endocrinol Metab. 2005

• Serum testosterone should be measured in men with type 2 diabetes with symptoms suggestive of testosterone deficiency4

1Laaksonen DE, et al. Diabetes Care. 2004;27:1036–1041; 2Kupelian V, et al. J Clin Endocrinol Metab. 2006;91:843-850; 3Muller M, et al. J

Clin Endocrinol Metab. 2005;90:2618-2623.; 4Wang C, et al. C, et al. Int J Impot Res. 2009;21:1-8.

Association Between Hypogonadism, Obesity, and Insulin Resistance

Leydig cells� Increased insulin resistance affects cells

Low testosterone

Adipose tissue� Increased number of adipocytes in obese and type-2 diabetic men

� Greater aromatase activity

� Increased metabolism of testosterone to estradiol

Pituitary and hypothalamus� Estradiol inhibits LH/FSH secretion

FSH = follicle stimulating hormone; LH = luteinizing hormoneCohen PG. Med Hypotheses. 1999;52(1):49-51; Kapoor D, et al. Clin Endocrinol (Oxf). 2005;63(3):239-250;

Pitteloud N, et al. J Clin Endocrinol Metab. 2005;90(5):2636-2641.

Role of Testosterone in Erectile

Function• Screening

– 19% of men with ED are known to have low testosterone1

– 23-50% of patients are non-responsive to PDE5 inhibitors2

– Patients failing PDE5 inhibitors may warrant screening for low testosterone

• Causes of ED include several factors3

– Psychogenic

– Neurogenic

– Endogenic

– Vasculogenic

• Animal models suggest that the erectile pathway is testosterone dependent4

– Nitric oxide is necessary for penile erection

1. Bodie J, et al. J Urol. 2003;169:2262–2264; 2. Salonia A, et al. Curr Med Res Opin. 2003; 19:241-262;

3. Yassin AA, Saad F. J Androl. 2008; 29:593-604; 4. Shabsigh R. Aging Male. 2004; 7:312-318.

Number Treated

• 2009 1.2 million

• 2013 2.3 million

Endocrine Today : April 2016

Source FDA

FDA Concerns Prompt New Warning

• FDA Concerns Have Decreased

• Use of TRT

• • Risk of CVD, VTE and stroke – FDA

• requires boxed warning on all TRT

• products since 6/14, 3/15.

• • Decision made based on 4 trials (Vigen, Finkle,

• Basaria, Xu).

• • All with methodological flaws or misleading

• results.

• • Concern with inappropriate use and use in

• aging men

Increased Use of TRT

• Increased opioid use

Increased incidence of co-morbidities

• • Obesity

• • DM

• • HIV/AIDS

• • Increased steroid abuse

• • Stress

Heart and Testosterone

Testosterone & the Heart

• 4 Studies Concluded Increased CV Risk

• Vigen et al

– Concluded that there was a doubling of risk

– 29 different Medical groups demaned it be

retracted for faulty design & Calculation

– The group admitted errs and came out with

correct conclusions

– Results the opposite of original conclusions

Basaria et al

Showed Increased CV Events

• Mean age was 74

• Subjects had Serious Chronic Diseases

– High Percentage of Subjects

– Diabetes, Abn. Lipids, HTN, Obesity and Pre-

existing Heart Disease

• Selected Patients with Mobility Problems

The Studies that prompted FDA

• Finkle Study:

– Too small to be significant

• Xu Study

– Meta analysis that was flawed

Hypogonadal Males Treated with

Testosterone

• Shores et al studied 1031 Males at VA

– Showed increased mortality in the untreated

group compared to treated group

• 20.75 compared to 10.3%

• Glueck et al. showed that males with

undiagnosed hypercoaguable states had more

DVTs and PE in the treated group

Morganthaler AnalysisMayo Clinic

• Reviewed over 100 studies.

– Found the same 4 suggesting Increased CV Risk

• The rest had no evidence of increased CV risk.

– Showed improved CV Function.

– Increased Benefit for older men.

Morganthaler, A et al Mayo Clin Proceed Feb 2015;2:p224-251

Medical Letter

• Adverse reactions to TRT include:

• Gynecomastia

• Acne

• Edema

• Polycythemia

• No Convincing evidence of increased Prostate Cancer

• Needs further study for CVD

JAMA Vol: 315#14; pp12-14

QTc interval

• Felt to be measure of Cardiac Repolarization

– Short QTc goes with fewer cardiac problems

• Shortens in Men age 9-50

• Starts to prolong at age 60 or with low T

• Studies show Men with Low T have long QTc

• Charbit, van Noord & Picori Giraldi have

shown hypogonadal males treated with

Testosterone have short QTc intervals

Hypogonadal Males Treated with

Testosterone

• Shores et al studied 1031 Males at VA

– Showed increased mortality in the untreated

group compared to treated group

• 20.75 compared to 10.3%

• Glueck et al. showed that males with

undiagnosed hypercoaguable states had more

DVTs and PE in the treated group

J.Brent Muhlestein, MD

Intermountain Heart Institute

American Heart Ass. Scientific Session

March 2016

• No increase in major CV events including MI

or CVAs in healthy men > age 50.

– 1472 men age 52 – 63 followed for 3 years

• Decrease in MI, CVA and death was seen.

• European Heart Journal 2015

Mayo Clinic Study

30 day Re Hospitalization Rate

• 6372 non surgical Pts. age 66+ with Low T

Re hospitalization rate

• 9.8% re hospitalization for pts on TRT

• 13% for those not treated with TRT

Mayo Clin Proc 5,2016:91(5) 587-595

Wallis Study

• 10,311 men aged 66+ on TRT for 5 years

• Men on TRT had lower death rate and CV

events.

• Short term Rx increased Mortality & CV

• Long Term Associated with lower Death rate

and CV events

Wallis CJ et al Lancet Diabetes Endocrionol

http://dxdoi.org/10.1016/s2213-8587(16)00112-1

Multiple Articles Show Benefit of TRT49

• Low levels of endogenous testosterone and increased mortality 8

• Low testosterone levels and increased incidence of coronary

• artery disease 6

• Low testosterone level correlates with increased severity of

• coronary artery disease 4

• Low endogenous testosterone level and increased carotid

• intima-media thickness 8

• TRT decreases obesity 6

• TRT improved cholesterol levels (meta- analysis) 3

• TRT improves glycemic control 6

• TRT decreases markers of inflammation 8

Corona Meta-analysis of TRT and

CV events (MACE)

• Available evidence “does not support a causal

• Role between testosterone supplemental and

adverse CV events when hypogonadism is

properly diagnosed and replacement therapy

correctly preformed”.

• Corona G, et al. Expert Opin Drug Saf. 2014;13: 1327-51.

American Association of Clinical

Endocrinologists and American college

of Endocrinology

• There is no compelling evidence that testosterone

• therapy either increases or decreases cardiovascular

• risk.

• • Large-scale prospective randomized controlled trials

• on testosterone therapy, focusing on cardiovascular

• benefits and risks, are clearly needed.

• • As with therapeutics in general, common sense,

• experience, and an individualized approach are

• recommended

• Endocr Pract. 2015;21:1066-1073

50 + Years of Testosterone Rx

• Why After 50 years do we need more studies?

• 2 very Large VA Studies had shown:

1. Decreased Mortality in Men Using T

2. No Increase in CVD Incidents

• Could it be the Advent of the more Expensive

Patch and Gel?

50 + Years of Testosterone Rx

• Steven Nissen?

– This story should not be about the use of

testosterone therapy, it should be about the abuse

of testosterone therapy“

– “I think until proven otherwise, we should

consider these supplements to be unsafe for

men”.

– “More studies are needed”

Have you or a loved one suffered a Heart

attack, Stroke or DEATH from Testosterone

replacement?

Injured by Testosterone Supplements?

Call now for money you deserve.

The Legal Examiner

• Cleveland Clinic Dr. Warns about Testosterone Risks

• Posted by Gregory SpizerOctober 29, 2014 11:23 AM

• Comments Off

• inShare

• Renowned Cleveland Clinic cardiologist Steven Nissen, MD is advising men to stop taking medication to treat low testosterone (low-T) caused by aging.

• In his recent article, “Why Your Low-T Medications May Not Be Safe,” Nissen warns men looking to counteract the effects of aging not to start taking low-T medications, and he suggests current users discontinue use.

• A U.S. Food and Drug Administration (FDA) advisory panel recently recommended that doctors limit the use of testosterone drugs to men diagnosed with low-T as a result of a medical condition, such as pituitary or testicular disease.

• The panel’s recommendations would exclude millions of men who are taking low-T drugs to treat low testosterone levels caused by aging.

• The FDA panel also recommends that low-t drug makers explore possible testosterone-related heart attack and stroke risks. A 2014 Journal of the American Medical Association (JAMA) study suggested that men taking testosterone had an increased risk of suffering a heart attack or stroke.

• Nissen recommends that men taking testosterone drugs talk to their doctor to determine whether it is medically necessary. He discourages men from relying on it to feel or look younger, as they may be putting their health at risk.

• A number of men who suffered a heart attack or stroke while taking low-T drugs have filed testosterone lawsuits. Men who want to take legal action after suffering a testosterone heart attack or stroke are urged to contact a testosterone lawyer to discuss their legal rights.

• Tags: testosterone heart attack, testosterone lawyer, testosterone stroke

Signs of Low Testosterone

• Incomplete sexual development

• Breast discomfort, gynecomastia

• Increased body fat

• Reduced muscle bulk and strength

• Lack of effect of PDE5 inhibitors for erectile dysfunction

• Low BMD

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

• Low or zero sperm count

Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.

1. Do you have a decrease in libido (sex drive)?

2. Do you have a lack of energy?

3. Do you have a decrease in strength and/or endurance?

4. Have you lost height?

5. Have you noticed a decreased enjoyment of life?

6. Are you sad and/or grumpy?

7. Are your erections less strong?

8. Have you noticed a recent deterioration in your ability to play sports?

9. Are you falling asleep after dinner?

10. Has there been a recent deterioration in your work performance?

Screening for Low T

If the answer is yes to question 1 or 7, or at least three of the other questions, low

testosterone may be present.

Morley JE, et al. Metabolism. 2000;49(9):1239-1242.

Androgen Deficiency in Aging Males (ADAM) Questionnaire

Symptoms of Low Testosterone

Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.

Male Hormonal StatusChanges With Age as SHBG Increases

Gray A, et al. J Clin Endocrinol Metab. 1991;73:1016-1025.

<3435-44 45-54 55-64 65-74 >75

Age (y)

Total Testosterone SHBG

~288 ng/dL ~576 ng/dL

As SHBG increases with age, levels of free testosterone decrease

Diurnal Variation in Serum Total

Testosterone LevelsTo

8 am noon 4 pm 8 pm midnight 4 am 8 am

Older Men

Young Men

Bremner WJ et al. J Clin Endocrinol Metab. 1983;56:1278-1281.

SHBG = sex-hormone binding globulin.

Adapted from Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:422-

Circulating Testosterone

2% 38% 60%

Diagnosing Hypogonadism

• Signs and symptoms1

• Clinical laboratory diagnostic tests1

– Total testosterone levels (<300 ng/dL)*

– Bioavailable testosterone (<70 ng/dL)

– Free testosterone (<50 pg/mL)

• Screening tools

– ADAM (Androgen Deficiency in the Aging Male) Questionnaire2

– AMS (Aging Males' Symptoms) Scale3

– MMAS (Massachusetts Male Aging Study) Questionnaire4

*Most frequently used lab test for the diagnosis of hypogonadism.

1. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8:439-456; 2. Morley JE, et al. Metabolism. 2000;49:1239-1242; 3.

Moore C, et al. Eur Urol. 2004;46:80-87; 4. Smith KW, et al. Clin Endocrinol. 2000;53:703-711.

Additional Tests

• LH and FSH

– To ascertain whether cause is primary or

secondary

• Serum prolactin

– High prolactin levels may suggest presence of

pituitary tumor

Braunstein GD. Testes. In: Basic & Clinical Endocrinology. 5th ed. Stamford, CT: Appleton &

Lange; 1997:403-433. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.

Further Diagnostic Recommendations

Primary Hypogonadism� Karyotype to rule out Klinefelter syndrome

Secondary Hypogonadism� Measure serum prolactin, iron saturation, and other pituitary hormones

� Obtain MRI if

� Severe secondary hypogonadism (TT <150 ng/dL)

� Hyperprolactinemia

� Other pituitary-hormone deficiency (panhypopituitarism)

� Symptoms/signs of tumor-mass effect(headache, visual-field defect, or impairment)

TT = total testosterone

MRI = magnetic resonance imaging.

Testosterone Replacement Therapy

Testosterone-Replacement Therapy

Dosing and Administration

Intramuscular Injection

�Testosterone enanthate or cypionate

�75-100 mg weekly or 150-200 mg every 2

Transdermal Patches (Nonscrotal)

�2.5-7.5 mg applied nightly for 24 hours*

Transdermal Gels 1%

5-10 g applied daily (5-10 mg testosterone systemically

absorbed)

Buccal Tablets

�30 mg tablet applied to the buccal mucosa

every 12 hours

Pellets

�150-450 mg implanted subcutaneously every

3-6 months†

Transdermal Gels Are the Most

Commonly Prescribed Form of TRT

IMS NPA; 2008.

*Schematic representation; not an actual study.

Testosterone Levels After

Replacement With Gel or Injection*

Gel Injection

Time (d)

0 3 5 7 12 17 21 30 34

Normal range of

testosterone

Testosterone

Sub-therapeutic levels

of testosterone

300 ng/dL

1000 ng/dL

TRT Replacement

• Injections

– Mood swings

– Polycythemia – Strokes or AMI

• Oral Tablets – Methyl Testosterone

– Toxic Hepatitis

• Skin Patches

– Skin Reactions

• Pellets

– Infection

• Gels

– Transference to partner

Monitoring After Initiation of

Testosterone Replacement Therapy

Adapted from Bhasin, et al. J Clin Endocrinol Metab. 2006;91:1995-2010 and Rhoden EL, et al. N Engl J Med.

2004;350:482-492.

What About Prostate Cancer?

• Geriatric patients may be at an increased risk for prostatic

hyperplasia and prostatic carcinoma

• PSA levels in hypogonadal men are often abnormally low1,2

– TRT may increase PSA levels reflecting normalization and typically

plateau within 12 months of initiating therapy

– Increases in PSA levels beyond this warrant further screening

1. Bhasin, et al. J Clin Endocrinol Metab. 2006;91:1995-2010; 2. Miner M, et al. Postgrad Med. 2008;120:130-153.

Original Basis for Concern• Castration caused prostate cancer regression, and T administration caused progression

(Huggins C, et al., 1941)

• Case reports of conversion of occult cancer into clinically apparent lesions

Current View• Prevalence rate of prostate cancer in TRT patients similar (1.1%) to that found in general

population (over 6-36 months)

• Despite decades of work, there is no compelling evidence that testosterone has a causative

role in prostate cancer

• Prostate cancer prevalence increases as T levels decline

• Studies show no significant differences in testosterone levels between those who develop

prostate cancer and those who do not

Future Direction

• The Institute of Medicine and National Institute of Aging are embarking on studies to further

evaluate causality

Testosterone and Prostate Cancer Concerns and Current Views

T = testosterone; TRT = testosterone-replacement therapy.Huggins C, Hodges CV. Cancer Res. 1941;1:293-297; Liverman CT, Blazer DG. Executive Summary. In: Testosterone

and Aging: Clinical Research Directions. Washington DC: The National Academies Press; 2004:1-9.

Rhoden EL, Morgentaler A. N Engl J Med. 2004;350(5):482-492.

� Serum PSA concentration >4 ng/mL

� An increase in serum PSA >1.4 ng/mL within any 12-month period of T

replacement

� A PSA velocity of >0.4 ng/mL/yr using the PSA level at 6 months after

initiation of T replacement as the reference

� Only applicable if PSA data are available for a period

>2 years

� Detection of prostatic abnormality on DRE

AUA = American Urological Association; DRE = digital rectal exam; IPSS = International Prostate

Symptom Score; PSA = prostate specific antigen.

Reasons for Urological Consultation

Benefits of TRT

• Testosterone

• and Depression

• An overview of older studies shows

• mixed results regarding the relationship

• between testosterone levels in men and

• depression1

• However several well-controlled studies

• indicate that endogenous testosterone

• levels are lower in depressed aging men

• than in healthy subjects *2,3

• In particular, low bioavailable

• testosterone levels in aging men

• correlate strongly with depression *3

• 1 Margolese HC, J Geriatr Psychiatry Neurol 2000;13(2):93-101.

• 2 Schweiger et al. Psychosom Med 1999;61(3):292-6 .

• 3 Barrett-Connor et al. J Clin Endocrinol Metab 1999;84(2):573-7.

• Testosterone

• and Cognitive Function

• Cognitive measures demonstrate significant

• correlation with plasma bioavailable

• testosterone levels in some, but not all

• studies

• Plasma testosterone levels influence the

• performance of cognitive tasks with positive

• correlations with spatial tests and negative

• correlations with verbal tests

• Plasma testosterone is lower in men with

• Alzheimer’s Disease than in healthy men

• 1Yliskoski et al. 1999.2Morley et al., 1997.3Perry et al.

• 2001.4Kimura et al., 1994. 5Christiansen and Knussmann,

• 1987.6Ahlbom et al. 2001.7Hammond et al. 2001.8Hogervorst et

• al. 2001.

Goals and Benefits of Testosterone

Replacement Therapy

• Improve libido and improve erectile function

• Improve body mass and strength

• Improve bone mineral density

• Improve energy level

• Improve mood/sense of well-being

Petak SM, et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.pdf.Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.Wang C, et al. J Clin Endocrinol Metab. 2000;85:2839-2853. Katznelson L. Baillières Clin Endocrinol Metab. 1998;12:453-470.

Improvement in Sexual Function

Parameters• 90-day study in 406 hypogonadal men

– Randomized, multidose, multicenter, active, and placebo controlled

• Significant improvement from baseline vs placebo included

– Motivation (P<0.05)

– Performance (P<0.05)

– Desire (P<0.01)

– Spontaneous erections (P<0.001)

• An additional open-label extension study supported these

Steidle C, et al. J Clin Endocrinol Metab. 2003; 88:2673-2681.

Dean J, et al. Rev Urol. 2004;(suppl 6):S22–S29.

Significant and Sustained Improvement in Sexual

Performance* With TRT(in 12-month extension study following 90-day pivotal trial)

0 3 9 12

*Based on average number of days with orgasm, ejaculation,

intercourse, masturbation, or erection in response to sexual activity.

Open-label Extension Study Month

↑↑↑↑ 76.6%P<0.001

Significant Improvement in Body

Composition With TRT(in 12-month extension study following 90-day pivotal trial)

Dean J, et al. Rev Urol. 2004; 6(suppl 6):S22–S29.

Fat Mass

0 3 6 9 12

Lean Body Mass

0 3 6 9 12

−4.84 lbP<0.0001

↓↓↓↓3.96 lbP<0.0001

Results after 36 Months of

TRT Therapy: Sexual Function

Sexual desire

0 6 12 18 24 30 36

Satisfaction with erection

0 6 12 18 24 30 36

p=0.000

Wang C, et al. J Clin Endocrinol Metab. 2004;89(5):2085-2098.

Results after 36 Months TRT Therapy: Bone Mineral Density

Change Hip BMD

−−−−0.01

0 6 12 18

363024

Change Spine BMD

0 6 12 18

363024

Results after 36 Months of TRT Therapy: Effect on

Positive Moods

Negative Moods

p=0.0022p=0.0013

0 6 12 18 24 30 360 6 12 18 24 30 36Month

Contraindications and Relative Contraindications of Testosterone Replacement Therapy

• Known or suspected prostate cancer

• Known or suspected carcinoma of the breast

• Prostatic hyperplasia in geriatric patients

• Sleep apnea (may exacerbate condition; patients should be

treated for sleep apnea first [CPAP])

• Edema with or without congestive heart failure

• Patients with polycythemia

• Is not indicated for women, has not been evaluated in

women, and must not be used in women.

Contraindications� Male breast cancer

� Prostate cancer (known or suspected)

� Use in pregnant or breast-feeding women

� Known or suspected sensitivity to ingredients used in T delivery systems

Precautions� Benign prostatic hyperplasia (BPH)

� Lower urinary tract symptoms (LUTS)

� Edema in patients with preexisting cardiac, renal, or hepatic disease

� Gynecomastia

� Precipitation or worsening of sleep apnea

� Azoospermia

� Testicular atrophy

Testosterone-Replacement TherapyContraindications and Precautions

BMD = bone mineral density; DRE = digital rectal exam; PSA = prostate specific antigen;

TRT = testosterone-replacement therapy.

Conclusions

• Hypogonadism in adult men is often unrecognized

• Known diseases of aging are associated with an increased

decline in testosterone

• Low testosterone is characterized by changes in the

body fat/lean muscle ratio; bone mineral density; cognition,

memory, and mood; and sexual desire and function

• Before prescribing be sure that it is needed

• Check Levels to be sure that they do not go too high.

What about Women

Women - Symptoms

• Symptoms:

– Decreased sexual desire

– Decreased sexual thoughts & fantasies

– Decreased strength

– Decreased genital response & orgasim

– Decreased lubrication

What about Women

• Can they have low testosterone levels?

• 43% age 18 – 59 suffer from sexual

dysfunction

Low Testosterone Levels

in Women

• Age Total Free

• <50 <25 ng/dl <1.5 pg/ml

• >50 <20 ng/dl <1.0 pg/ml

Guay, A & Davis, S

http://www.bumc.bu.edu/sexualmedicine/publications/testosterone

-insufficiency-in-women-fact-or-fiction

Women and Testosterone

• All women make testosterone

– ¼ from Ovaries

– ¼ from Adrenals

– ½ Peripheralally

• In US no testosterone product is indicated in

women.

Women and Testosterone

• Precursors of testosterone

– DHEA

– DHEA Sulfate

• DHEA has been suggested as treatment for

• Over the counter

Endocrine Society Guidelines

• Put together a task force to create Guidelines

• Unable to come up with guidelines

• Too many things were not standardized

Guidelines – British Society for

Sexual Medicine

YES NO

Sexual Distress +

Psychosexual problems

Counseling Counseling

May consider Pharmacology

Sexual distress+

Medical Problems

Treat Medical problem Pharmacology may be

appropriate

Postmenopausal

Psychosexual

Sexual Distress

Counseling

Pharmacology may be

appropriate

Generalized therapy not

recommended

SHBG > 160 Testosterone not appropriate Pharmacology may be

appropriate

Thank You!

testosterone replacement in adultssyllabus.aace.com/.../presentations/seibel-testosterone.pdf ·...

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