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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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.

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HISTORY

• Testosterone first used clinically in 1937, only
  2 years after its 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.

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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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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.
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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 yet initiated
  to assess risks and benefits of
  testosterone-replacement 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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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.

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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.

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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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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-Replacement 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 T
herapy and Recommendations for Monitoring N Engl
J Med 2004 350482-492
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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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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

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Low Testosterone Level

• Measure FSH and LH
• Prolactin level
• TSH
• MRI of Pituitary if FSH/LH low or not elevated?

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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.

Liverman. Testosterone and agingWashingon
DCNational Academies Press.
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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 (600-700ng/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
• Can check serum testosterone level at any time

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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

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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)

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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.

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Follow-up of The Testosterone-Replaced 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

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WHATS NEW?

• Gonadal Steroids and Body Composition, Strength,
  and Sexual Function in Men
• NEJM 36911, September 12, 2013

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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 intraabdominal-fat areas.

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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.

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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.

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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

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Guidelines continued

• Do not start testosterone therapy in patients
  with breast or prostate cancer,
• palpable prostate nodule or induration or PSA
  gt3 without urologic evaluation.
• Severe LUTS
• HCT gt50
• Untreated OSA
• Severe CHF

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CASE I AND II REVIEW