Treatment of The Hypogonadal
Male
William Abeyta MD
Associate Professor of Medicine
AVAH/UNM SOM
OBJECTIVES
• Understand the clinical features of male
hypogonadism.
• Discuss possible causes.
• Interpret laboratory tests and how to order
them in different clinical scenarios.
• Review and describe the hypothalamicpituitary-testicular axis.
• Understand general principles of treatment
OBJECTIVES
• Describe the various testosterone
preparations.
• Understand the monitoring required when
using testosterone replacement.
• Identify complications of treatment.
Why do we need testosterone?
• In men, testosterone plays a key role in
the development of male reproductive
tissues such as the testis and prostate as
well as promoting secondary sexual
characteristics such as increased muscle,
bone mass, and the growth of body hair. In
addition, testosterone is essential for
health and well-being as well as the
prevention of osteoporosis.
HISTORY
• Testosterone first used clinically in 1937,
only 2 years after it’s Nobel Prize-winning
discovery.
• Testosterone prescribing is escalating at
startling rates creating a nearly $2 billion
annual market.
• Surging off-label use (anti-aging, sexual
tonic, bodybuilding or doping.
HYPOGONADISM
• Defined as the failure of the testes to
produce androgen, sperm, or both.
• Testosterone production decreases with
advancing age: 20% of men older than 60
and 30-40% of men older than 80 have
serum testosterone levels that would be
subnormal in their younger male
counterparts.
Case I
82 yo male presented to his new PCP with a
chief complaint of back pain.
The pain began suddenly when he helped
move a pool table at the senior center one
month prior to this visit.
Despite worsening pain to the point that he
could no longer walk very well, he had refused
to come in for evaluation.
He had no neurologic/bowel/bladder complaints
Case I
Meds: APAP, viagra.
Tobacco: 1PPD x 65 years
ETOH: none x 5 years, formerly heavy use
PMH:
1. Right hip fracture with ORIF 2 years ago
2. Esophageal stricture with multiple
dilations in the past.
FH: neg for osteoporosis that he was aware of.
Case I
PE: normal vitals
Neck: no nodes or thyromegaly
Lungs: decreased BSs throughout
CV: RRR without M/R/G
Abd: soft without hepatosplenomegaly or masses
Back: Marked thoracic kyphosis with tenderness
at T12 and L1
Testicles: 5cm bilat, normal pubic hair
CXR: Hyperinflation
Thoracic and lumbar spine films: compression
fractures of T12 and L1 appearing acute.
Lab:
Hct 38, MCV 95, nl WBC/plts
Calcium 9.2
SPEP neg for paraprotein
PSA <.03
Normal TSH/prolactin
Free testosterone 0.3 (11-25)
Total testosterone 32 (241-827)
LH 14.1 (1-7)
FSH 61.2(1.4-15)
PTH normal
DXA: >4SD hip&spine
Case II
66 year-old male presented to his resident MD
for general medical f/u. He had been on
testosterone injections for 2 years for primary
hypogonadism. His last Hct was one year prior
and had been 50. The patient complained of
fatigue, headaches, and dizziness.
On exam his face appeared very flushed. Lab
testing showed a Hct of 62%.
Hypogonadism
• Low levels of testosterone along with other
specific signs and sxs. (diminished libido,
ED, reduced muscle mass/bone density,
depression, anemia)
• Affects 2-4 million males in the US.
Hypogonadism
• Only 5% of men currently receive rx
• Recent interest in rx d/t media attention,
marketing of new preparations, “desire of
baby boomers” to maintain vigor and
health into their more mature years.
• Considerable controversy regarding
indications for testosterone
supplementation in aging males.
Hypogonadism
• No large-scale, long-term studies yet initiated to
assess risks and benefits of testosteronereplacement rx in part d/t theoretical risk of
possible stimulation of prostate cancer by
testosterone.
• It is estimated that a study would need to include
6000 elderly hypogonadal men randomly
assigned to receive testosterone or placebo for
6 years in order to determine whether rx
increases risk of prostate cancer by 30%.
Snyder.Hypogonadism in Elderly Men-What To
Until the Evidence Comes.N Engl J Med 2004;350:440-442
Gonadotrophins-FSH, LH
• Secreted by gonadotrophs in the anterior
pituitary gland.
• FSH and LH secreted in pulsatile fashion.
(pulsatile LHRH release results in pulsatile
LH and FSH release).
• FSH has a longer half-life so levels
fluctuate less throughout the day.
• Regulate testicular and ovarian function.
Testicular Effects of FSH and LH
• LH controls testosterone production by
Leydig cells.
• FSH in conjunction with intratesticular
testosterone stimulates seminiferous
tubules to produce sperm.
• FSH and LH required for sperm production
but only LH necessary for testosterone
production.
The Testes
• 60% of testicular volume accounted for by
seminiferous tubules.
• Prepubertal testis 2cm in length and 2ml in
volume.
• Testes average 4.6cm in length in adults
but range from 3.5-5.5 cm according to
Harrisons Textbook of Medicine.
• 4-7cm in UpToDate.
Testes
• Advanced age does not influence
testicular size. (therefore significance of
small testes is the same at all ages of the
adult)
• Testis size varies among ethnic groups.
• Asian men have smaller testes than
western Europeans, independent of
differences in body size.
Serum Testosterone Levels
• Diurnal rhythm.
• Values are 30% higher near 8am vs later in the
day.
• Normal range varies among laboratories.
• Usual range for young men is 300-1000ng/d.
• In general values < 220-250 are clearly low in
most laboratories.
• Values 250-350 should be considered borderline
low.
Signs and Symptoms of
Hypogonadism
1.
2.
3.
4.
Diminished libido
Erectile dysfunction
Difficulty achieving orgasm
Diminished intensity of orgasmic
experience
5. Diminished sexual penile sensation
Signs and Symptoms of
Hypogonadism
Other
1. Diminished energy/sense of well being
2. Increased fatigue
3. Depressed mood
4. Anemia
5. Diminished bone density/muscle mass
Risks of TestosteroneReplacement Therapy
1. Coronary Artery Disease: few if any
data support a causal relation between
higher testosterone levels and heart
disease. High testosterone levels may
actually have a favorable effect on the
risk of CV disease. Studies have not
demonstrated an increased incidence of
CV disease or events such as MI, stroke,
or angina. Rhoden, et al. Risks of Testosterone-Replacement
Therapy and Recommendations for Monitoring
N Engl J Med 2004; 350:482-492
Risks of TestosteroneReplacement Therapy
2. Lipid Profiles: Available data
inconsistent (supraphysiologic doses
appear to lower HDL).
Some variability may be explained by
dosage.
Present data taken together suggest that
testosterone replacement therapy within
the physiologic range is not associated
with worsening of the lipid profile.
Rhoden, et al. Risks of Testosterone-Replacement
Therapy and Recommendations for Monitoring
N Engl J Med 2004; 350:482-492
Risks of TestosteroneReplacement Therapy
3. Polycythemia: Higher testosterone levels
act as a stimulus for erythropoiesis.
Injections appear to be associated with a
greater risk than topical preparations.
No testosterone-associated thromboembolic
events have been reported to date.
Risks of TestosteroneReplacement Therapy
4. BPH: Prostate volume DOES increase
significantly during testosterone-replacement
therapy (determined by ultrasonography) mainly
during the first 6 months.
Poor correlation between prostate volume and
urinary sxs.
Multiple studies fail to demonstrate exacerbation of
voiding sxs attributed to BPH during
testosterone supplementation.
Risks of TestosteroneReplacement Therapy
5. Prostate Cancer: Prospective studies have
demonstrated a low frequency of prostate
cancer in association with testosteronereplacement rx.
Occult prostate cancer in men with low
testosterone levels appears to be substantial
with higher grade prostate cancers.
No compelling evidence to suggest men with
higher testosterone levels are at a greater risk or
that treating men who have hypogonadism with
exogenous androgens increases this risk.
Rhoden, et al. Risks of Testosterone-Replacement
Therapy and Recommendations for Monitoring
N Engl J Med 2004; 350:482-492
*Prostate cancer becomes more
prevalent at the time of a man’s
life when testosterone levels
decline.
Risks of TestosteroneReplacement Therapy
6. PSA: Studies have inconsistently shown
a rise in PSA in testosterone treated
patients (0.3-0.4ng/ml)
A substantial rise in PSA should arouse
suspicion that a prostate cancer has
developed.
Risks of TestosteroneReplacement Therapy
7. Hepatic Effects: Oral preparations of
testosterone reported to lead to
hepatotoxic effects and neoplasia,
including benign and malignant tumors.
IM injections and topical preparations of
testosterone do not appear to be
associated with hepatic dysfunction and
routine monitoring of LFTs is unnecessary
for men on these forms of replacement rx.
Risks of TestosteroneReplacement Therapy
8. Sleep Apnea: Testosterone-replacement
therapy has been associated with the
exacerbation of sleep apnea or with the
development of sleep apnea (Seen in men
treated with higher doses of parenteral
testosterone and have other risk factors
for sleep apnea). Probably by central
mechanisms rather than by anatomical
changes in the airway.
Miscellaneous Effects of
Testosterone
•
•
•
•
•
Breast tenderness and swelling
Testicular size and consistency diminish
Fertility is diminished
Skin reactions with topicals
Pain, bruising, soreness, furuncles with
testosterone injections
• Fluid retention
• Acne, oily skin
• No data to suggest acceleration of male-pattern
baldness.
Evaluation of the Possible
Hypogonadal Male
Physical exam: focus on whether or not sexual
development is consistent with the patient’s
age.
• Testicular size: 4-7cm in length.
• Normal musculature
• Dense pubic hair and in a diamond pattern.
• Beard should be full and dense
• Chest and other body hair should be present.
Laboratory Tests
Serum Testosterone Measurement:
• Am total serum testosterone level
• Check free testosterone level in obese
males and older males.(changes in SHBG)
• Repeat measurement if low or borderline
level of testosterone
Low Testosterone Level
•
•
•
•
Measure FSH and LH
Prolactin level
TSH
MRI of Pituitary if FSH/LH low or not
elevated?
Who To Treat With TestosteroneReplacement Therapy?
• Testosterone should be given ONLY to a
male who is hypogonadal as evidenced by
a low testosterone level.
• There is insufficient evidence that
testosterone benefits elderly males without
clearly abnormally low testosterone levels.
Liverman. Testosterone and aging:Washingon DC:National
Academies Press.
Baseline Exam/Tests Before
Beginning Treatment With
Testosterone
•
•
•
•
•
Voiding history
History of sleep apnea
Perform DRE
Baseline PSA and HCT/hemoglobin
GU referral if PSA over 4.0 or abnormal
prostate exam
Testosterone Preparations
1. Testosterone Esters: injectable testosterone
2. Transdermal:
Nonscrotal patch
Testosterone Gel
Ointment
Solution
3. Buccal tablet
4. Pellet (Testopel Implant)
Testosterone Esters
Testosterone Esters: Injectable testosterone
• Testosterone enanthate and cypionate
used for years in treatment of testosterone
deficiency.
• Begin with 200mg IM every 2 weeks.
• Can change to 100mg every week if
fluctuations in libido, mood, energy.
Testosterone Esters: Injectable
testosterone
• Measure testosterone midway between
injections and value should be mid-normal
(600-700ng/ml)
• Reduce dose if higher values obtained.
• Disadvantage is fluctuations in mood,
energy and libido in many patients
Nonscrotal Patch
•
•
•
•
One body patch is available (Androderm)
Worn on arm, torso, or thigh
Start with 4mg patch
Can check serum testosterone level at any
time
Testosterone Gel
• Apply once per day
• Takes a month to reach normal levels and
remain steady throughout 24 hours.
• Can check serum level at any time of day
Buccal Tablet
• Approved by FDA June, 2003 (Striant)
• Applied and adheres to a depression in
the gum above the upper incisors and
releases testosterone across the buccal
mucosa
COST $$$$
Testosterone cypionate inj 1ml (200mg)
$10.14 ($20.28/month)
Testosterone 2 mg patch (1) $7.06
4mg patch (1) $14.11
($211.18/month and $423.30/month)
Cost $$$$
Testosterone gel 1% 1.25GM/ACT (75GM)
$212.62/month
Testosterone gel 1.62% 20.25mg/ACT(75GM)
$412.40/month
Buccal testosterone 30mg (60) $517.50/month.
Follow-up of The TestosteroneReplaced Male
• Follow-up visit in 2-3 months for efficacy
evaluation
• Assess urinary sxs/sleep apnea
• Perform DRE at ~3 months and q year
thereafter
• Testosterone level at 2-3 months
• PSA at 3 months and q year thereafter
• HCT at 3 months and than yearly
WHAT’S NEW?
“Gonadal Steroids and Body
Composition, Strength, and Sexual
Function in Men”
NEJM 369;11, September 12, 2013
Methods
• 198 healthy men 20-50 years of age given goserlin to
suppress endogenous testosterone and estradiol.
• Randomly assigned to receive placebo gel, or
testosterone gel in different doses daily for 16 weeks.
• Another 202 healthy men received goserline, placebo gel
or testosterone gel and anastrozle to suppress
conversion of testosterone to estradiol.
• Primary outcomes were changes in percentage of body
fat and in lean mass.
• Thigh muscle area and strength and sexual function also
assessed along with subcutaneous and intraabdominalfat areas.
Results
• % of body fat increased in groups receiving
placebo or low dose of testosterone daily without
anastrozole.
• Lean body mass and thigh-muscle area
decreased in men receiving placebo and in
those receiving low dose testosterone daily
without ansatarozole.
• Leg press strength fell only with placebo
administration.
• In general, sexual desire declined as the
testosterone dose was decreased.
Conclusions
• The amt. of testosterone required to maintain
lean mass, fat mass, strength, and sexual
function varied widely in men.
• Androgen deficiency accounted for decreases in
lean mass, muscle size, and strength.
• Estrogen deficiency primarily accounted for
increases in body fat.
• Both testosterone deficiency and estrogen
deficiency contributed to the decline in sexual
function.
Summary: Endocrine Society
Clinical Practice Guidelines for
testosterone replacement therapy.
• Diagnosis of androgen deficiency only in
men with consistent symptoms and signs
with unequivocally low serum testosterone
levels.
• Measure morning total testosterone.
• Confirm with repeat total testosterone and
free or bioavailable testosterone using
accurate assays
Guidelines continued
• Do not start testosterone therapy in
patients with breast or prostate cancer,
palpable prostate nodule or induration or
PSA >3 without urologic evaluation.
Severe LUTS
HCT >50%
Untreated OSA
Severe CHF
CASE I AND II REVIEW