Considerations for the diagnosis and treatment of testosterone deficiency in elderly men

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Considerations for the diagnosis and treatment of
testosterone deficiency in elderly men

• Mohammed Kazi, MD et al
• The American J of Medicines
• ?????

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Abstract (1)

• Increased longevity and population aging will
  increase the number of men with relative
  testosterone deficiency, as systemic levels of
  testosterone decrease by about 1 each year.
• Androgen deficiency should only be diagnosed in
  men with definite signs and symptoms, accompanied
  by low total testosterone levels measured in the
  morning by a reliable assay.
• Current practice guidelines recommended
  testosterone replacement therapy for symptomatic
  men with low testosterone levels to improve BMD,
  muscle mass and strength, sexual function, and
  quality of life.

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Abstract (2)

• Testosterone replacement is not recommended for
  all older men with low testosterone levels, and
  should be avoided in patients with prostate or
  brest cancer, hyperviscosity, erythrocytosis,
  untreated obestructive slepp apnea, or severe
  heart failure.
• The goal of all available testosterone treatment
  modalities (IM, nongenital patch or gel,
  bioadhesive buccal and oral testosterone, and
  pellets) is to achieve serum testosterone level
  in the mid-normal range during treatment.
• Cost varied widely among these preparations and
  may limit their use.
• Patient received testosterone replacement therapy
  should be re-evaluated 3 months after
  testosterone initiation and at least annually
  thereafter.

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Male hypogonadism

• Defined as failure of testes to produce normal
  amounts of testosterone, combined with signs and
  symptoms of androgen deficiency.
• Systemic testosterone levels fall by about 1
  each year in men.
• Therefore, with increasing longevity and the
  aging of the population, the number of older men
  with testosterone deficiency will increase
  substantially over the next several decades.

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Testosterone and Sex-hormone-binding globulin
(SHBG)

• Serum testosterone levels decrease progressively
  in aging men, but the rate and magnitude of
  decrease vary considerably.
• Approximately 1 of healthy young men have total
  serum testosterone level below 250 ng/dL in
  contrast, approximately 20 of healthy men over
  age 60 years have serum testosterone below this
  value.
• Baltimore Longitudinal Study on Aging reported
  that average annual decrease of total serum
  testosterone of 3.2 ng/dL in men gt53 years (ie,
  about 1 per year based on a lower limit of
  normal of 325 ng/dL)
• Massachusetts Male Aging Study, SHBG increases by
  1.2 annually.
• Most circulating testosterone is bound to SHBG or
  to albumin.
• Free and bioavailable testosterone levels
  decrease with age to a greater degree than is
  reflected by the total testosterone level.

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Etiology of male hypogonadism (1)

• LH and FSH decrease with age in healthy men
• The most common cause of androgen deficiency in
  elderly men is hypogodotropic hypogonadism.
• Leydig cell function in the testes decrease with
  aging and is affect by several medications,
  including glucocorticoids, spironolactone,
  opiates, and ketoconazole.
• Neuroleptic drugs that cause hyperprolactinemia
  can inhibit the release of gonadotropin-releasing
  hormone, leading to hypogonadotropic
  hypogonadism.
• Medical conditions associated with a high
  prevalence of low testosterone levels include
  type 2 DM, ESRD, osteoporosis or low-trauma
  fracture, infertility, diseases of the sellar
  region, weight loss due to malignancy or human
  immunodeficiency virus (HIV), and other less
  common chronic disorders.

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Diagnosis of male hypogonadism

• Questionnaires to assess symptoms of androgen
  deficiency.
• Other findings suggestive of testosterone
  deficiency in men include hot flashes and
  diaphoresis, very small or shrinking testes
  (adult testes are usually about 4.5 cm x 2.8 cm),
  reduce need for shaving, breast discomfort and
  gynecomastia, decreased spontaneous erections,
  reduced sexual desire and activity, reduced
  muscle bulk and strength, inability to father
  children (due to low or zero sperm counts),
  height loss, low BMD, and low-trauma fractures.
• Less specific findings include decreased energy,
  depressed mood, mild anemia, and diminished
  physical or work performance.

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Table 1 Testosterone Deficiency in Aging Men

• 1. Are your erection less strong ?
• 2. Do you have a decrease in libido (sex drive)?
• 3.Do you have a lack of energy?
• 4. Are you falling asleep after dinner?
• 5. Has there been a recent deterioration in your
  work performance?
• 6. Have you noticed a decreased enjoyment of
  life?
• 7.Do you have decrease in strength and/or
  endurance?
• 8. Have you noted a recent deterioration in your
  ability to play sports?
• 9. Are you sad and/or grumpy?
• 10. Have you lost weight?
• Positive test if the answer is yes to question 1
  or 2, or to any 3 other questions

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Endocrine Society recommended

• Measured Mid-morning total serum testosterone
  level for older men with clinical symptoms and
  signs
• Peak testosterone levels occur between 7-10 AM
• Diet does not significantly affect the serum
  testosterone level, but a high insulin level
  (following a high CHO meal) can lower SHBG.
• Heavy alcohol consumption can decrease serum
  testosterone
• Smokers have a total and free testosterone levels
  5-15 higher than nonsmokers.
• SHBG levels are decreased in moderate obesity,
  hypothyroidism, glucocorticoid use, and nephrotic
  syndrome, and increased in hyperthyroidism,
  anticonvulsant use, cirrhosis, and other
  conditions.

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Table 2 Alterations in Sex-Hormone Binding
Globulin (SHBG) Concentrations

• Increased SHBG levels
• Aging
• Hyperthyroidism
• Liver cirrhosis
• Use of estrogens
• Use of anticonvulsants
• HIV infection
• Decreased SHBG levels
• Moderate obesity
• Use of glucocorticoids, progestins, and
  androgenic steroids
• Nephrotic syndrome
• Hypothyroidism

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Testosterone levels

• 2 serum testosterone is unbound or free.
• Testosterone can rapidly dissociate from albumin,
  all non-SHBG-bound testosterone is considered
  bioavailable.
• Total testosterone, the lower limit of the normal
  range is considered to be around 315 ng/dL (11
  nmol/L) free testosteorne 6.5 ng/dL,
  bioavailable testosterone, 140 ng/dL
• Free testosterone indextotal T/SHBG

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DDX of hypogonadism

• If initial total T is low (lt300 ng/dL or 10.4
  nmol/L), the measurement should be repeated, as
  30 men with initially low level will have a
  normal level upon repeat testing.
• Men with true deficiency states demonstrate
  persistently low T
• LH and FSH should be measured
• 2nd hypogonadism is a common cause of androgen
  deficiency in older men.
• Intra- and perisella lesionslow total T, LH,
  FSH, high prolactin, MRI scan

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History and physical (symptoms and signs)
Morning total T
Normal T
lt300 ng/dL
Follow up
Low T
Exclude reversible illness, nutritional
deficiency Repeat T use free or bio T, if
suspect altered SHBG LHFSH SFA if fertility
issue
Normal T, LHFSH
Confirmed low T e.g. Total T lt300 ng/dL or free
or bio T lt Normal (e.g. free T lt5 ng/dL)
T testosterone
SFA seminal fluid analysis
Low T, low or normal LHFSH (20)
Low T, high LHFSH (10)
Prolactin, iron, other pituitary Hormones, MRI
Karyotype Klinefelter Syndrome
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2 Cross-sectional analysis

• Belstress study (2322 men aged 35-59 years)
  Siblos study (358 men aged 25-45 years) showed
  androgen receptor polyglutamine tract
  polymorphism encoded by a CAG repeat of variable
  length in exon 1 of the AR gene might play an
  important role in subject variability in serum
  (free) testosterone in healthy men
• CAG repeat length was positively associated with
  serum total testosterone in both study
  populations.
• Increased CAG repeat length was associated with
  increased free testosterone levels.

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Therapy problems (1)

• In older men, controversial
• Some experts favor treating symptomatic men with
  Tlt300 ng/dL, others favor a threshold 200 ng/dL.
• In either case, for men with classical androgen
  deficiency signs and symptoms accompanied by
  persistently low T, testosterone replacement
  therapy is recommended to improve sexual
  function, BMD, and sense of well-being, and to
  induce and maintain senondary sex
  characteristics.
• Testosterone also is suggested for men with low
  testosterone levels and erectile dysfunction.
• Short-term adjunctive therapy with testosterone
  levels and weight loss to improve muscle strength
  and promote weight gain.
• Testosterone also should be considered in men
  with low testosterone levels who are receiving
  high dose glucocorticoid therapy in order to help
  preserve BMD.

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Therapy problems (2)

• Improved sexual activity scores and increased
  duration and frequency of nocturnal erections
  result from effective testosterone therapy in
  young hypogonadal men, but data are limited in
  older men
• Dose-dependent increases in hemoglobin
  concentration and in BMD are typically seen with
  testosterone therapy.
• CV effects of testosterone replacement appear to
  be neutral or mildly beneficial in young men. In
  older men, there is no convincing evidence that T
  therapy is either beneficial or harmful.
• Testosterone has minimal effect on serum lipids,
  on insulin sensitivity is controversial.

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Therapy problems (3)

• Hormone-dependent malignancies, such as prostate
  and breast cancer, may grow faster during
  testosterone therapy, not recommended in such
  patient.
• It also not recommended in pts with a palpable
  prostate nodule, a PSA gt 3 ng/mL, hyperviscosity,
  erythrocytosis (Hct gt50), untreated obstructive
  sleep apnea, severe benign prostatic hyperplasia.
• Additional factors may influence functional
  status and congnitive dysfunction

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Goal of testosterone therapy

• Achieve a serum testosterone in mid-normal range
• Testosterone enanthate or cypionate IM, 100mg qw
  or 200 mg biweekly.
• 5-10 mg nongenital testosterone patch applied to
  skin (away from pressure areas) HS
• Testosterone gel applied daily to nongenital skin
  (5-10 g dose)
• Bioadhesive testosterone tablets 30 mg to buccal
  mucasa q12h
• Oral testosterone undecanoate, injectable
  testosterone undecanoate, and testosterone
  pellets
• Testosterone doses are generally lower in older
  men, because metaboliized more slowly in the
  elderly.

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• Table 3 Testosterone Formulations
• Formulations Replacement
  Dosage Approximate Cost
• T esters T enanthate 100 mg/wk IM or 200
  mg q2 70/month
• T cypionate wk IM
  (200 mg
  per 2 weeks)
• Injectable long-acting T 1000 mg IM, then 1000
  mg at Not available in the US
• undecanoate in oil 6wk, and 1000
  mg every 12 wk
• Nongenital transdermal 5 mg, 1-2 patches
  every night 192/month
• T patch applied
  to nonpressure
• 
  areas (thigh, arm)
• Scrotal T patch 6 mg over 24 h
  applied daily 131 for 30 patches
• T gels 5-10 gm every
  AM 205-248/month (5
  g/d)
• Buccal T tablets 30 mg every 12 h
  190/month
• bioadhesive
• T pellets 4-6 200 mg
  pellets implanted 150 per 10 pellets
• SC

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• Table 3 Testosterone Formulations (continued)
• Formulation Advantage
  Disadvantage
• T esters Extensive clincial
  experience IM injection, uncomfortable
  Fluctuations
• T enanthate or Inexpensive
  in T levels and in libido,
  energy, mood
• Injectable long-acting T Corect symptoms of
  androgen deficency IM injection of a large
  volume (4ml),
• undecanoate requires less
  frequent administration more
  uncomfortable
• Nongenital transdermal Physiological circadian
  T levels, no Skin irritation
• T patch injection, Good adhesion, normal DHT
  levels
• Scrotal T patch Symptoms of
  androgen deficency are Scrotal skin needs
  to be shaved, High
• 
  corrected
  DHT levels
• T gels Physiological T
  levels, Little skin irritation Potential
  tranfer of T to women and
• Dose
  flexibilty, Musk odor
  children by contact (prevented by washing
• after 4-6
  hr), Costly, High DHT levels
• Buccal T tablets Steady-state T levels. No
  hand washing Twice daily, gum irritation, taste
• bioadhesive
  alteration, high DHT
• T pellets Symtpoms of androgen
  deficiency are Surgical incision needed and
  pellets may e
• corrected
  extrude

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Evaluation of patient after treatment (1)

• After therapy initiated, patient should be
  re-evaluated q3m and at least annually
  thereafter.
• Special attention should be directed to symptoms
  before and after treatment to determine
  satisfactory response and assess adverse effects.
• A mid-morning total serum testosterone level
  should be obtained, target range 350-700 ng/dL
  (12.3-24.5 nmol/L) for older men, range 400-500
  ng/dL (14.0-17.5 nmol/L)
• For injectable testosterone, serum level measured
  between injections.
• For transdermal testosterone patch, serum level
  measured 3-12 hrs after patch application.
• In buccal testosterone tablets, serum level
  measured immediately before application of a
  fresh system.
• For testosterone gel, checked anytime after at
  least 1 week of therapy.

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Evaluation of patient after treatment (2)

• Hematocrit should be measured at baseline, at 3
  months, and annually thereafter.
• If Hct gt54 , testosterone therapy should be
  discontinued.
• Digital rectal examination and PSA measurement
  performed before starting testosterone therapy.
• If PSA increases above 4 ng/mL, or by more than
  1.4 ng/mL within 12 months of treatment,
  urological consultation should be obtained.
• Evaluated for adverse drug effects-include
  excessive erythrocytosis, and fluctuations in
  mood or libido (injectable testosterone) skin
  reactions (patch) and alterations in taste and
  gum irritation (buccal testosterone)

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Summary (1)

• Aging in healthy men-associated with decrease in
  serum testosterone levels.
• Clinically significant androgen deficiency in
  older men is most often related to pituitary or
  hypothalamic abnormalities rather than to primary
  testicular failure.
• Challenge in diagnosing androgen deficiency in
  elderly is to link signs and symptoms to serum
  testosterone levels.
• Questionnaires for assessing symptoms of
  testosterone deficiency developed-also helpful in
  evaluating for depression.
• Measuring serum testosterone levels accurately
  and reliably is problematic, and measurement
  issues must be taken into consideration when
  making diagnosis..

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Summary (2)

• Total serum testosterone should be measured in
  the morning in a men with signs and symptoms
  consistent with androgen deficiency.
• If low, measurement should be repeated to confirm
  the diagnosis, because 30 false positive rate
  with initial screening.
• LH and FSH also should be measured to distinguish
  primary from secondary hypogonadism.

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Summary (3)

• Although large scale clinical trials in elderly
  men are lacking, testosterone replacement therapy
  is recommended in men with definite symptoms and
  signs of androgen deficiency in conjunction with
  a persistently low serum testosterone level.
• Several testosterone preparations are available,
  and selection of therapeutic modality should be
  based on considerations of personal preference,
  side effect profile, pharmacokinetics, and cost.
• Factors such as functional status and cognitive
  impairment may influence the decision to treat
  and the choice of therapy in older men.
• Following initiation of treatment, re-evaluation
  for efficacy and side effects should be performed
  after 3 months of therapy and at least annually
  thereafter.
• Additional research, including large scale
  clinical trials, to determine the short- and
  long-term benefits and risks of testosterone
  replacement are needed.