Treatment of The Hypogonadal Male

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Treatment of The Hypogonadal Male

• William Abeyta MD
• Associate Professor of Medicine
• AVAH/UNM SOM

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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 hypothalamic-pituitary-tes
  ticular axis.
• Understand general principles of treatment

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OBJECTIVES

• Describe the various testosterone preparations.
• Understand the monitoring required when using
  testosterone replacement.
• Identify complications of treatment.

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Roles of 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.

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HISTORY

• Testosterone first used clinically in 1937, only
  2 years after its Nobel Prize-winning discovery.
• Annual prescriptions for testosterone increasd by
  more than 5-fold from 2000-2011 reaching 5.3
  million prescriptions.
• Testosterone prescribing has created a nearly 2
  billion annual market.
• Surging off-label use (anti-aging, sexual tonic,
  bodybuilding or doping.

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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.

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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.

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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.

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Hypogonadism

• No large-scale, long-term studies available to
  assess risks and benefits of testosterone-replacem
  ent 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 2004350440-442
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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.

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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.

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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 lt 220-250 are clearly low in
  most laboratories.
• Values 250-350 should be considered borderline
  low.

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TABLE 2. Conditions associated with alterations
in SHBG concentrations
Conditions associated with decreased SHBG concentrations
Moderate obesity1
Nephrotic syndrome1
Hypothyroidism
Use of glucocorticoids, progestins, and androgenic steroids1
Conditions associated with increased SHBG concentrations
Aging1
Hepatic cirrhosis1
Hyperthyroidism
Use of anticonvulsants1
Use of estrogens
HIV infection
1Particularly common conditions associated with
alterations in SHBG concentrations.
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Signs and Symptoms of Hypogonadism

1. Diminished libido
2. Erectile dysfunction
3. Difficulty achieving orgasm
4. Diminished intensity of orgasmic experience
5. Diminished sexual penile sensation

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Signs and Symptoms of Hypogonadism

• Other
• Diminished energy/sense of well being
• Increased fatigue
• Depressed mood
• Anemia
• Diminished bone density/muscle mass

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Risks of Testosterone Therapy

• Coronary Artery Disease
• Adverse Events Associated with Testosterone
  Administration TOM Trial. NEJM July 8, 2010.
• -209 community-dwelling men 65 years of age or
  older, with limitations of mobility.
• -total serum testosterone level of 100-350ng/dl
  or a free testosterone level of lt50pg/ml
• -Randomly assigned to receive placebo gel or
  testosterone gel daily for 6 months.

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Results

• Trial terminated early because of a significantly
  higher rate of adverse CV events in the
  testosterone group than in the placebo group.
• Higher rates of cardiac, respiratory,
  dermatologic events in the testosterone treated
  group.
• 23 subjects in testosterone group as compared
  with 5 in the placebo group had
  cardiovascular-related adverse events.
• Testosterone group had significantly greater
  improvements in leg press and chest press
  strength and in stair-climbing while carrying a
  load.

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Risks of Testosterone-Replacement Therapy

• Association of Testosterone Therapy With
  Mortality, Myocardial Infarction, and Stroke in
  Men With Low Testosterone Levels

JAMA 11-6-2013 Volume 310
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• Retrospective national cohort study of men with
  low testosterone levels (lt300ng/dl) who underwent
  coronary angiography in the VA system between
  2005-2011.
• Primary outcome was a composite of all-cause
  mortality, MI, and ischemic stroke.

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Results

• At 3 years after coronary angiography cummulative
  percentages with events were 19.9 in the
  no-testosterone therapy group vs 25.7 in the
  testosterone therapy groupabsolute risk
  difference of 5.8.

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Limitations in the Study

• Observational
• Select group of patients in VA system undergoing
  angiography.
• Length of follow-up.

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Risks of Testosterone-Replacement 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 T
herapy and Recommendations for Monitoring N Engl
J Med 2004 350482-492
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Risks of Testosterone-Replacement 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.

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Risks of Testosterone-Replacement 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.

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Risks of Testosterone-Replacement Therapy

• 5. Prostate Cancer Prospective studies have
  demonstrated a low frequency of prostate cancer
  in association with testosterone-replacement 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 T
herapy and Recommendations for Monitoring N Engl
J Med 2004 350482-492
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Prostate cancer becomes more prevalent at the
time of a mans life when testosterone levels
decline.
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Risks of Testosterone-Replacement 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.

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Risks of Testosterone-Replacement 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.

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Risks of Testosterone-Replacement 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.

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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.

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Evaluation of the Possible Hypogonadal Male

• Physical exam focus on whether or not sexual
  development is consistent with the patients
  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.

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• Endocrine Society Guideline

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Who To Treat With Testosterone-Replacement
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.

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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

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Testosterone Preparations

• Testosterone Esters injectable testosterone
• Transdermal
• Nonscrotal patch
• Testosterone Gel
• Ointment
• Solution
• 3. Buccal tablet
• 4. Pellet (Testopel Implant)

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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.

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Testosterone Esters Injectable testosterone

• Measure testosterone midway between injections
  and value should be mid-normal (350-750ng/ml)
• Reduce dose if higher values obtained.
• Disadvantage is fluctuations in mood, energy and
  libido in many patients

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Nonscrotal Patch

• One body patch is available (Androderm)
• Worn on arm, torso, or thigh
• Start with 4mg patch
• Check level 3-12 hours after application of
  patch.

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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

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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
• Check level immediately before or after
  application of new system.

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Follow-up of The Testosterone-Replaced Male

• Follow-up visit in 3-6 months for efficacy
  evaluation and adverse effects.
• Assess urinary sxs/sleep apnea
• Perform DRE at 3-6 months and see below PSA rec.
• Testosterone level at 3-6 months.(aim for
  mid-normal range 350-750 ng/dl.)
• PSA at 3-6months and thereafter in accordance
  with guidelines for screening depending on age
  and race of patient.
• HCT at 3-6 months and than yearly(discontinue
  treatment if gt54)

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Obtain Urologic Consultation if

• Increase in PSA gt1.4ng/ml within any 12 month
  period of testosterone rx.
• PSA velocity of gt0.4ng/ml using PSA level after 6
  months of testosterone administration as the
  reference (if PSA data are available for a period
  exceeding 2 years)
• Abnl DRE
• AUA prostate sxs score gt19.

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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
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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.
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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.
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Lab Hct 38, MCV 95, nl WBC/plts Calcium 9.2 SPEP
neg for paraprotein PSA lt.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) DXA gt4SD hipspine PTH normal
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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.