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DIAGNOSIS
Only in men with consistent signs and symptoms with unequivocally low testosterone level
More specific symptoms
• Incomplete or delayed sexual development
• Decreased libido and sexual activity
• Decreased spontaneous erections
• Loss of body hair
• Small or shrinking testes
• Loss of height, low trauma fracture, low BMD
• Hot flushes, sweats
• Infertility
• Gynecomastia or breast discomfort
Less Specific symptoms • Fatigue and low energy
• Depression
• Poor concentration and
memory
• Decreased strength
• Decreased muscle mass
• Sleep disturbance
• Mild anemia
• Increased body fat and BMI
• Diminished physical activity
and work performance
www.sptimes.com
“My get up and go, got and went”
Chronic Diseases or Conditions Associated with
Low Testosterone
• Obesity • Type 2 diabetes, insulin resistance • Asthma, COPD, sleep apnea • Coronary atherosclerosis (link with abdominal visceral fat) • Chronic liver disease • Chronic renal failure • Inflammatory diseases
• Rheumatoid arthritis, Cohn's disease, ulcerative colitis • Corticosteroid and anabolic steroid use • HIV infection • Malnutrition • Hemochromatosis • Alzheimer’s Disease
Oh JY, et al. Diabetes Care. 2002;25:55-60; Stellato RK, et al. Diabetes Care. 2000;23:490-494; Barrett-Connor E, et al. Am J Epidemiol. 1990;132:895-901; Dobs AS, et al. Am J Med. 1988;84:611-616; Casaburi R, et al. Am J Respir Crit Care Med. 2004;170:870-878; Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987; Boyadjiev NP, et al. J Sports Med Phys Fitness. 2000;40:271-274; Straub RH, et al. Z Rheumatol. 2000;59(suppl 2):108-118; Svartberg J, et al. Respir Med. 2004;98:906-913.
Other causes of low
testosterone
• Eating disorders
• Excessive exercise
• Recreational drug use
• Long acting opiates: profound effect
• Methadone, buprenorphine
• Gonadotropin-Releasing Hormone (GnRH) in men with prostate cancer
• Shift work
Drugs and alcohol
alcohol
HIM Study*: Overall Conclusions
• Age-adjusted prevalence rate of low total testosterone levels was 38.4%
• Odds of having total testosterone <300 ng/mL or currently being treated for low testosterone are:
• 2.5 x higher if BMI 25 kg/m2
• 1.6 x higher with 5-unit increase
• 2.0 x higher for diabetes
• 1.8 x higher for hypertension
• 1.4 x higher for asthma/COPD
• 1.2 x higher for age 65
• 1.2 x higher with 10 y increase
*Mulligan T, et al. The HIM Study (Hypogonadism In Males): An Epidemiological Program to Estimate the Population Prevalence of Hypogonadism in Men over 45. Poster presented at the Annual Scientific Assembly of the American Academy of Family Physicians. October 13-17, 2004; Orlando, FL.
Changes in Serum Total Testosterone
Associated with Type 2 Diabetes
• Low total testosterone levels predict potential future
development of type 2 diabetes
Haffner SM, et al. Am J Epidemiol. 1996;143:889-897; Oh JY, et al. Diabetes Care. 2002;25:55-60;
Stellato RK, et al. Diabetes Care. 2000;23:490-494; Goodman-Gruen D, Barrett-Connor E. Diabetes
Care. 2000;23:912-918.
Treatment of hypogonadism with testosterone replacement therapy has not
been demonstrated to prevent the development of type 2 diabetes.
Diagnosis
Symptoms present AND
• Morning Total Testosterone level (<300)
• Confirmation with second measurement
• Within 2 hours of awakening in shift workers
• If low normal levels and suspect alterations in SHBG:
measure Free or bioavailable T
• Free Testosterone index: Testosterone/SHGB
• Do not evaluate during acute or sub-acute illness
What affects SHBG?
(sex hormone binding globulin)
• Obesity
• Old age
• Diabetes
• Thyroid disease: hyper or hypo.
• Acromegaly
• Certain drugs (highly protein bound drugs)
400
500
600
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800
900
800
1000
1200
1400
1600
1800
2000
2200
2400 20
040
060
080
0
Clock Time (hours)
Young (23-28 yrs) Old (58-82 yrs)
Bremner WJ, et al. Bremner WJ, et al. J Clin Endocrinol Metab.J Clin Endocrinol Metab.1983;56:12781983;56:1278--1281.1281.
Se
rum
Tes
tos
tero
ne
(n
g/d
L)
Diurnal Rhythms in Serum Diurnal Rhythms in Serum
Testosterone in Normal MalesTestosterone in Normal Males
• LH and FSH to differentiate Primary and
Secondary
• Secondary: Prolactin, iron saturation, TSH
• Primary: Karyotype
• DEXA if severe deficiency or low trauma
fracture
Further Evaluation
• Primary Hypogonadism:
• Low Testosterone
• High FSH and LH
• Secondary Hypogonadism:
• Low testosterone, (if <150ng/ml: REFER)
• Low or inappropriately Normal LH and FSH
• Check: prolactin , Sleep Apnea, genetic disorders, iron saturation (hemochromatosis)
Primary Hypogonadism (Primary Testicular
Disorder): Acquired Causes
• Medications
• Obesity
• Severe systemic illness
• Castration
• Hemochromatosis
• Respiratory disorders
• Idiopathic
• Neurodegenerative illnesses
• Malnutrition
• Trauma particularly head trauma
• Mumps orchitis
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.
Medications
associated with low Testosterone
• phenytoin
• Spironolactone
• Cimetidine
• Opiates
• Narcotics
• Glucocorticoids
• ketoconazole
Secondary Hypogonadism (Pituitary Failure): Acquired Causes or Conditions
• Pituitary adenoma
• Inflammatory diseases (rheumatoid arthritis, Cohn'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 abuse
Winters 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.
Potential Risks of Testosterone
Replacement Therapy
• Stimulation of growth in previously undiagnosed prostate cancer or growth of metastatic prostate cancer
• Increased risk of bladder outlet symptoms due to increase in prostate volume, can use Avodart or Proscar
• Edema in patients with preexisting cardiac, renal, or hepatic disease
• Erythrocytosis
• Precipitation or worsening of sleep apnea
• Acne and oily skin
• Reduced sperm production and fertility
Hijazi R, Cunningham G. Annu Rev Med. 2005;56:117-137; Cunningham G, Swerdloff R, et al. Summary from
the Second Annual Andropause Consensus Meeting, The Endocrine Society, 2001.
Contraindications of Testosterone
Replacement Therapy
• PSA>4ng/ml or >3ng/ml with high risk
• Untreated severe obstructive sleep apnea
• Severe lower urinary tract symptoms (American Urological Association/International Prostate Symptom Score 19)
• Hematocrit>50
• Heart Failure: poorly controlled/uncontrolled
• Those desiring fertility (may decrease spermatogenesis)
2010 Endocrine Society Clinical Practice Guideline
Baseline Testing in Symptomatic men
• Morning T level with confirmation (<300)
• Look for reversible secondary causes
• LH and FSH, Prolactin
• Testosterone <150, refer for further evaluation
• Other screening chemistries: CMP, CBC, TSH
• Men 40+ years baseline PSA>0.6ng/ml
• DRE and check PSA prior to initiation of treatment
PSA Testing Guidelines:
Resources
www.auanet.org/education/guidelines/prostate-cancer-detection.cfm
www.cancer.org
www.auanet.org
USPSTF: screen 55-69 based on individual decision and discussion regarding benefits and harms of testing. Against screening >age 70
2010 American Cancer Society Recommendations
last reviewed/revised April 2016
• Informed decision making to determine screening: Discussion recommended:
• If average risk with >10 year life expectancy • Start at age 50 (AUA/2013 & 2018 start age 55)
• High risk start screening at age 45
• PSA 4.0 as threshold for further evaluation
• PSA 2.5ng/ml-4.0ng/ml: after individualized decision making, interval screen annually
• PSA <2.5 screening interval: 2 years
AUA recommendations created 2013 and reaffirmed 2018
• AFTER INFORMED DECISION TO SCREEN
• Annual screening discouraged for those that choose to be
screened
• 55-69 consider every 2-4 years
• Men over 60 with PSA<1.0 screen at 4 yr. interval
• Age 70-75 if PSA<3.0 can safely stop screening
Multiple approaches subsequent to a PSA test (e.g., urinary
and serum biomarkers, imaging, risk calculators) are
available for identifying men at risk for PCA or more
aggressive disease
2010 American Cancer Society Recommendations
• High Risk Patients:
• African American (>2x whites)
• Less often Asian-Amer. and Hispanic than Caucasians
• Father or brother with prostate cancer at age<65
• Provide information:
• beginning age 45
• 40 if multiple family members
• (with early PCA) • BRCA gene increases risk in some men
April 2013 Early Detection of Prostate Cancer:
AUA Guidelines
Recommendation against routine screening: <40 years old (evidence based strength C)
Average risk men: age 40-54 (evidence based strength C)
Men with <10-15 year life expectancy
Men age 70+ years
(some men who are in excellent health may benefit from screening)
High Risk: <55 years: decisions should be individualized
available on the AUA.org
April 2013 Early Detection of Prostate Cancer:
AUA Guidelines
Age 55-69 years
Shared Decision Making Recommended
The greatest benefit of screening in this age group
Informed Decision Making Guidelines
cdc.gov
• Understands the nature and risk of prostate cancer
• Understands the risks of, benefits of, and alternatives to
screening
• Participates in the decision to be screened or not at a level
he desires.
• Makes a decision consistent with his preferences and
values
Resources for patients
• Urologyhealth.org
• Auanet.org: wall charts and brochures to download, you
tube video
• http://www.urologyhealth.org/media-center/is-prostate-
cancer-screening-right-for-me
• Screening-Fact-Sheet-Nov-2017.pdf
Prostate Cancer Informed Decision Making
Video for Patients (I highly recommend this)
http://www.youtube.com/watch?feature=player_embe
dded&v=Vg9iBOzIo38
•
• Prostate Cancer: Informed Decision Making Videos
Tools for Individualized Risk Assessment of
Prostate Cancer (Age 55-95)
http://deb.uthscsa.edu/uRORiskCalc/Pages/calcs.jsp
http://www.asco.org/sites/www.asco.org/files/psa_pco_decision_aid_71612.pdf
www.cancer.org/prostatemd has video for clinicians and more
April 2013 Early Detection of Prostate Cancer:
AUA Guidelines
Those who have participated in shared decision making and
decided on screening: :Strategies to reduce harm
• Increase screening interval: every 2 years or more
• Intervals for rescreening can be individualized by a
baseline PSA level
• Men over 60 with PSA <1.0ng/ml, longer interval
screening (4 years)
• Age 70-75 with a PSA< 3ng/ml Discontinue screening
• Biopsy threshold of 10
Age Dependent PSA Values
Age PSA level(ng/ml)
40-49 <2.5
50-59 <3.5
60-69 <4.5
70-79 <6.5
Reasons to Obtain Urological
Consultation
• Serum PSA >4 ng/ml (American Cancer Society 2010)
• PSA increase >1.4 ng/mL within any 12-month period of T replacement
• A PSA velocity of >0.4 ng/mL/year
• using the PSA level after 6 months 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 prostate symptom score >19
Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(16):1995-2010.
PSA levels affected by:
• Age
• Prostate size (BPH)
• DRE
• Acute illness
• Ejaculation within
24-48 hours
• Prostatitis
• Lower urinary symptoms LUTS)
• Prolonged sitting/bike riding/pelvic vibration
PSA
• The trend from one year to the next is
extremely important
• No more than a 15% increase per year is expected
• PSA increase >0.75ng/ml in a year
with PSA 4-10
• 0.4ng/ml per year in younger men with PSA<4
• Free PSA if PSA between 4.0-10
• (AUA 2009)
Treatment
• Suspect and test if symptomatic
• Baseline labs and exam
• Use prostate cancer risk calculator
• Discuss expectations, risks and benefits
• INFORMED CONSENT
• Refer or go for it
Testosterone Replacement for Male Hypogonadism
FDA-INDICATED USES
As part of its 2015 advisory on cardiovascular risk, the FDA also issued
a statement clarifying that testosterone therapy is approved specifically
for men with low testosterone levels caused by disorders of the testicles,
pituitary gland, or brain that cause hypogonadism (i.e., genetic
disorders, damage from chemotherapy or infection, or pituitary tumors)
and not for men with age-related low testosterone.38 Physicians should
be aware that prescribing testosterone for low testosterone levels due to
aging constitutes off-label use.
This is not what to expect!
Treatment choices
• Gels: Axiron, Androgel, Testim, Fortesta
• Injections: testosterone cipionate or enanthate (Depo-testosterone)
• Transdermal patches : Androderm, Testoderm
• Buccal, bioadhesive tablets: Striant
• Testosterone Pellets: Testopel
• Injectable long-acting T undecanoate in oil (Aveed) every 10 weeks. REMS program
• ORAL TAB (Jatenzo): FDA indicated only if due specific genetic disorders or pituitary gland damaging tumors. Black box warning, may be available end of 2019
• T. enanthate (Xyosted) SQ weekly injection
Xyosted
• Dose 50-100 mg weekly SQ
• Start 75mg and adjust based on
response
• Black Box Warning: BP, CV risk
• Only indicated in hypogonadism
associated with structural or genetic
etiology
Treatment Choices: Gels
• Pumps, tubes, packets
• Flexibility of dosing
• Ease of application
• Good skin tolerability
• Disadvantages: transfer to females or children from skin
to skin contact
• Poor absorption in some
GELS: what you need to know
• Must avoid skin to skin contact with others
• Axillary preps: do not share deodorant, recommended to
apply AFTER deodorant
• If burning, try applying before deodorant.
• Timing of showers: Levels maintained if 4-6 hours after
application
• Let it dry prior to putting on clothes
Testosterone Gel Mean Steady State Concentrations on
Day 30
Testo
ste
ron
e c
on
cen
trati
on
(ng
/dL
)
Time (hours) after application
0 4 8 12 16 20 24
Lower limit of normal range
Upper limit of normal range
5 g T-Gel 10 g T-Gel
0
400
800
1400
200
600
1000
1200
AndroGel® [prescribing information]. Marietta, GA: Solvay Pharmaceuticals, Inc.; December 2007.
When to check levels
• Buccal formulation: immediately before or after
application of fresh system
• Gels: must be on treatment at least a week
• Patches: 3-12 hours after application
• Testosterone, (cypionate or enanthate) • 150-200 mg IM every 2 weeks or 75-100mg weekly
• Check a level one week after the 4th injection
• Usually 10 to 14 days between injections, sometimes 3-4 weeks
• Patients will tell you when their injection is wearing off
• Always pay attention to time of blood draw in relation to last injection. • Levels vary depending on dose and time between injections
INJECTIONS: goal 400-700ng/ml
Testosterone Enanthate 250 mg
Administered IM Every 3 Weeks
Time (weeks)
Seru
m t
esto
ste
ron
e
co
ncen
trati
on
(n
g/d
L)
0
400
800
1000
1400
0 3 15
200
600
1200
6 9 12
Lower limit of normal range
Upper limit of normal range
Nieschlag E, Behre HM. Pharmacology and clinical uses of testosterone. In: Testosterone: Action, Deficiency, Substitution. Third Edition. Cambridge University Press 2004. 405-422.
IM = Intramuscular
Monitoring therapy
• Response to treatment
• Adverse affects
• Compliance with treatment
• Testosterone and hematocrit: after 3-6 months of treatment and annually
• DEXA after 1-2 years if osteoporotic or have low trauma fracture
Monitoring therapy
• Buccal testosterone tablets: ask about change in taste,
check gums and oral mucosa
• Injections: fluctuations in mood or libido, and rarely
cough after injection
• Patches: skin irritation
• Gels: Cover with a shirt and wash with soap and water
before skin to skin contact
• Pellets: infection, fibrosis, pellet extrusion
The goal is to treat to physiologic doses not
super doses
Too Little Too Much
ifoughtthelaw.cementhoriz
on.com
Darth Vader kills
Elmo
www.guzer.com/pictures/darth_el
mo.php
PSA changes expected
Average PSA change 3-6 months after start
testosterone
• 0.3 ng/ml in young
• .44 ng/ml in older men
• Increase >1.4 ng/ml over a 3-12 month period:
REFER
Hematocrit > 54%
• STOP Treatment until decreases
• Evaluate for hypoxia
• Sleep apnea
• Reinitiate therapy at reduced dose
Despite treatment for hypogonadism, 39% had
sub therapeutic T levels
Hypogonadism defined as Total Testosterone level <300 ng/dL
0
5
10
15
20
25
Nu
mb
er o
f T
reat
ed S
ub
ject
s
Total Testosterone Levels (ng/dL)
EVIDENCE BASED
• Endocrine Society’s Clinical Guidelines: Remarks
• Need to recognize considerable disagreement among
experts due to lack of evidence base to reach consensus
recommendations
EVIDENCE
• BMD: inconsistent and imprecise results
• Body composition: significantly greater increase in LBM
and greater reduction in fat mass. (Body weight did not
differ)
• Muscle strength and physical function: Improvement
in grip strength (consistent)
• lower extremity muscle strength (inconsistent)
Evidence continued
• Quality of Life: inconsistent, with improvement in
physical function domain score
• Depression: inconsistent and imprecise data
• Cognition: imprecise data
Endocrine Society’s
Clinical Guidelines:
• Against: treating all older men with low T
• Individualize
• Recommendations for short term treatment
• for men receiving high doses of glucocorticoids
• HIV and weight loss
Summary
• Hypogonadism is often underdiagnosed. The prevalence increases with age and certain chronic medical conditions including obesity and type 2 diabetes
• Men complaining of decreased libido, diminished erectile function, changes in energy or mood, and those with osteopenia or osteoporosis should be evaluated for hypogonadism
• Serum total testosterone should be measured on 2 separate occasions in the morning
• Serum PSA, hematocrit, bone densitometry, digital rectal examination, and AUA symptom scores or IPSS aid in deciding to prescribe TRT and in monitoring
