Andropause

1
Andropause
2
Testosterone production

• produced in the testicular Leydig cells
• stimulated by the pituitary LH secretion
• young adults ? diurnal variation
• ageing men ? ?diurnal variation

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Testosterone production

• circadian rhythm in normal young men
• peak levels 2225 nm at 06.0008.00 h and a
  nadir of 1518 nm in the early evening

4

• Specific actions of Testosterone (T)
• After entering the target cells (in the
  hypothalamus, pituitary, testis and wolffian
  duct)
• T is directly bound to the androgen receptor
  (AR) and the complex T-AR binds to specific DNA
  sequences

5

• Specific actions of 5a -Dihydrotestosterone
  (DHT).
• After entering the target cells (in the
  urogenital sinus, urogenital tubercle, and
  several additional androgen target tissues)
• T is metablized to 5-DHT by the enzyme
  5a-Reductase type 2.

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Testosterone measurements

• 2 as free testosterone
• 54 with low affinity to albumin and other
  proteins
• 44 with high affinity to SHBG

Bioavailable or non-SHBG bound
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Testosterone measurements

• The measurement of the free testosterone fraction
  by equilibrium dialysis ? the gold standard
• Bioavailable testosterone measurements by RIA of
  the supernatant
• correlate well with obtained by equilibrium
  dialysis
• a circadian rhythmicity that is blunted with
  ageing

8
Testosterone measurements

• Calculated free testosterone
• determine the free component of testosterone
  based on the total levels of testosterone, SHBG
  and albumin
• very good correlation with equilibrium dialysis
  measures

9
Changes in testosterone with age

• begin to decline in the late 3rd or early 4th
  decade and diminish at a constant rate
• the rate of decline
• cross-sectional studies 0.50.8 per year
• longitudinal studies Massachusetts Male Ageing
  Study (MMAS Feldman et al., 2002) 1.6 per year

10
Changes in testosterone with age

• SHBG rising with ageing
• 1.3 per year in a cohort aged 40 years and over
  (Feldmanet al., 2002).
• Calculated free testosterone levels decrease 23

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Physiological changes in the HPT axis with age

• ?Leydig cell number
• ? testosterone
• ? LH levels

• alteration in the feedback mechanisms within the
  HPT axis

? amplitude of LH pulses asynchrony between LH
release and testosterone secretion
? testosterone in ageing men may not elicit a
compensatory LH response
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Prevalence of androgen deficiency in the ageing
male

• difficult to estimate due to the heterogeneity of
  the studied populations
• differing methods of estimating testosterone
  levels (total, free estimates)
• lack of consistency of nominal values for
  defining biochemical hypoandrogenism

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Prevalence of androgen deficiency in the ageing
male

• 30 of men aged 4689 years
• total testosterone levels below 10.4 nm Swartz
  Young, 1987
• 20 of healthy men 60 years
• total testosterone lt 11 nm Kaufman Vermeulen,
  1997 Harman et al., 2001 Tenover, 2000

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Prevalence of androgen deficiency in the ageing
male

• 1/3 of men classified as normal according to
  their total testosterone levels would be
  incorrectly labelled
• free testosterone, as measured by equilibrium
  dialysis,
• Morley et al ., 2002.

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Factors influencing testosterone levels

• No correlation between exercise patterns
• Smoking /-
• Alcohol ? upon the pattern and duration of usage

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Factors influencing testosterone levels

• Alcohol ? upon the pattern and duration of usage
• Acutely ? inhibits testosterone production
• Sustained stable alcohol intake in healthy older
  men ? not influence
• Chronic alcoholic liver disease ? Hypogonadism
• effect androgen metabolism
• ? SHBG levels

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Factors influencing testosterone levels

• Cohorts in the MMAS
• men 40 years
• 710 years of follow-up

• a reduction
• in testosterone of 1015

• chronic illness
• medication
• obesity
• excessive alcohol in all age

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Factors reducing testosterone levels

• Medications
• such as opiates (change in LH pulsatility)
• anticonvulsants (hepatic enzyme induction)
• Acute systemic illness
• affect steroidogenesis / spermatogenesis
• Both benign and malignant lung disease
• DM , CHD , BPH
• Depression

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Why is testosterone so important?

• helps to build protein
• essential for normal sexual behavior and
  producing erections
• affects many metabolic activities
• production of blood cells in the bone marrow
• bone formation
• lipid meta-bolism
• carbohydrate metabolism
• liver function
• prostate gland growth

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Potential benefit of testosterone replacement
therapy
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Bone

• Men 30 yrs undergo a gradual loss in bone
  mass
• 2 million men in the USA have osteoporosis
• 1 in 8 men over age 50 will have an
  osteoporosis-related fracture
• Severe T deficiency results in bone loss e.g.
  congenital hypogonadism, androgen deprivation
  therapy for prostate cancer

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Bone

• Risk factors for osteoporosis
• family history of osteoporosis,
• smoking,
• excessive alcohol intake,
• physical inactivity,
• poor nutrition,
• vitamin D deficiency,
• inadequate calcium intake,
• hypogonadism,
• use of some medications (e.g., glucocorticoids,
  anticonvulsants)

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Bone

• Testosterone act
• directly on androgen receptors in bone cells or
• indirectly by modulating the action of cytokines
  or growth factor metabolism
• Androgen as well as estrogen
• critical for the development of a normal male
  skeletal mass.
• affect bone metabolism
• both may be reduced with aging and hypogonadism.

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Bone Estrogen

• very important in bone development in males
• derived from the aromatization of T to estradiol
  and androstenedione to estrone
• with inactivating mutations of the aromatase gene
  develop osteopenia and osteoporosis that improve
  with estradiol therapy

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• Synthesis of the male sex hormones in Leydig
  cells.
• P450SSC, 3b-DH, and P450c17 are the same enzymes
  as needed for adrenal steroid hormone synthesis.
• 17,20-desmolase is the same as 17,20-lyase of
  adrenal hormone synthesis..

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Bone Estrogen

• Estradiol
• more potent
• sensitivity and accuracy are marginal
• Total estradiol
• affected by SHBG
• Free estradiol or bioavailable estradiol
• most informative.

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Bone TRT

• At least 5 published placebo-controlled trials
• 13108 men treated for 336 months with low or
  low-normal baseline T levels
• reported the effects of TRT on
• bone turnover markers
• bone density in older men.

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Bone TRT

• No trial examined the effects of TRT on fracture
  rates.
• Because TRT ?estradiol , it is likely that some
  of the effect is mediated by estrogen receptors

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Cognitive Function

• T could exert its actions through androgen
  receptors ? modulate serotonin, dopamine,
  calcium, and acetylcholine signaling pathways.
• ? neurite arborization to facilitate
  intercellular communication
• Most of the effects on are thought to be
  domain-specific.

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Cognitive Function

• Moffat et al.
• 407 men , 5091 years at baseline f/u 10 years,
• higher free T ? better scores on visual and
  verbal memory, visuospatial functioning, and
  visuomotor scanning
• ?rate of decline in visual memory
• In another study, low estradiol high total and
  bioavailable T
• predicted better performance on several tests of
  cognitive function

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Cognitive Function Results from 5
placebo-controlled trials

• Some found better verbal memory and spatial
  cognition but no significant differences in other
  cognitive domains.
• Sih et al.
• found no effect of T administration on cognition.

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Body Composition, Strength, and Function

• skeletal muscle mass ?35 between 20 80 yrs
• sarcopenia / loss of strength leads to
• impairment of physical function
• loss of mobility
• falls and fractures
• loss of independence
• depression

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Body Composition, Strength, and Function

• ? nitrogen retention.
• ? protein synthesis and muscle hypertrophy.
• ? fat-free mass and decreases in fat mass
• Multiple placebo-controlled trials in both
  younger and aging men with T deficiency
• changes in muscle strength and body composition
  in response to exogenous T.

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Body Composition, Strength, and Function

• The effects of androgen on fat mass
• stimulation of lipoprotein lipase
• a reduction in stem cells that differentiate into
  adipose cells
• In hypogonadal males
• TRT usually reduces it somewhat ( typically by
  23 kg).
• both younger and aging males

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Mood and Depression

• T ? modulate the serotonin and dopamine pathways.
• T levels and changes in mood has not been studied
  extensively.
• In cross-sectional studies, Barrett-Connor et al.
  
• ? Hamilton Depression Index with increasing age,
  and correlated with ?bioavailable T

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Sexual Function

• T ? NO? ? ?penile bloood flow
• most potent relaxor of corpora cavernosal smooth
  muscle
• The T concentrations to maintain normal sexual
  activity appear to be in the low-normal range,
  slightly less than 300 ng/dl in healthy young
  men.

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Sexual Function

• gt 10 placebo-controlled trials
• relatively young populations
• T may be beneficial with low baseline T
• with normal baseline T ? no effect on erection
  and inconsistent effects on libido
• Aging is associated with a reduction in sexual
  activity
• ? How much T deficiency is unclear
• Multiple vascular and neurological conditions
• Co-morbid medical conditions.

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Potential risk for TRT
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Cardiovascular

• ? protective effects of estrogen, harmful effects
  of T
• T VS cardiovascular disease ? N / ? effect
• Most of these trials
• short duration (4 weeks to 36 months)
• small number
• TRT ? LDLand HDL?

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Red Blood Cells

• T erythropoietin secretion?
• direct effect on the bone marrow
• TRT ? usually found Hct gt52
• larger doses of parenteral T esters

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Prostate

• the majority of prostate carcinomas require
  androgens for growth.
• Androgen ablation ? regression of metastatic
  prostate carcinoma
• But cancer cells that survive ? relapse and
  androgen-independent disease.

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Prostate

• 2 prospective cohort studies and 10 nested
  case-control studies
• ? T levels with future development of prostate
  cancer
• No positive correlation
• A meta-analysis of placebo-controlled trials (S.
  Bhasin, personal communication)
• more prostate cancer diagnoses among men with TRT

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Prostate

• 5a-reductase inhibitor ( finasteride )
• ?prostate volume 1520
• ? progression of BPH, urinary retention, and need
  for invasive treatment
• TRT 5a-reductase inhibitor
• ? progression of BPH and need for invasive
  treatment of BPH

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Conclusion of TRT

• The goals of TRT
• reduce symptoms and prevent morbidity.
• T levels are vary depending on the target organs
• T on libido and erectile function low-normal
  range.
• T on skeletal muscle dose dependence
• Absolute contraindications to TRT
• prostate or breast cancer.

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Conclusion of TRT

• T on CA prostate and other prostate outcomes
• remains poorly defined
• Another approach to ?the risk of developing CA
  prostate
• TRT with a chemopreventive agent ( finasteride
  TRT)

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Testosterone delivery systems
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Testosterone delivery systems

• Oral
• rapid metabolism by the liver
• Oral bioadhesive T tablet
• adheres to the gum.
• achieved T levels within 24 h.

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Testosterone delivery systems

• Parenteral
• lipophilic esters
• a depot with slow release when injected
  intramuscularly
• Peak levels usually are supernormal and nadir
  values may be subnormal.
• The variation in T levels ? mood changes.
• erythrocytosis more frequently than transdermal
  therapy

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Testosterone delivery systems

• T Pellets
• maintain T levels for 34 months
• desirable in younger men
• carries risk in aging men.
• Transdermal Gels
• applied daily to nongenital skin.
• plateau within a few days
• relatively stable when the gel is applied daily
• skin rashes are uncommon.

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Testosterone delivery systems

• Transdermal Patches
• scrotal patch.
• applied daily
• peaked 35 h after application
• nonscrotal T patches
• daily to the arm, hip, or abdomen
• peak 38 h later

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Testosterone delivery systems
53
Investigational androgens SERMs

• stimulate tissues normally androgen-responsive
  (SERMs)
• skeletal muscle, bone, external genitalia, and
  the brain
• avoid others
• stimulation of the prostate

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MONITORING

• Physiological serum T levels (400600 ng/dl)
• Should be done 13 months after starting therapy
• clinical response and potential side effects
• at 3, 6, and 12 months and then annually.

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MONITORING

• Side effects of therapy
• acne
• worsening of lower urinary tract symptoms
• cause an occult prostate cancer to increase in
  size
• ?erythrocytosis
• worsening sleep apnea.
• gynecomastia
• 17-a alkylated androgens can cause liver toxicity
  
• Lipid disturbances usually not significant may
  result

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MONITORING

• Bone mineral density
• at baseline and every 12 years in men with T
  scores below 2
• Hct , PSA, digital rectal and breast examination
• at baseline, at 3, 6, and 12 months, and then
  annually in men aged gt 50.

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MONITORING

• Annual PSA measurements digital rectal
  examination
• African Americans
• men who have a first-degree relative with
  prostate cancer
• PSA gt 4.0 ng/ml or ?gt 0.45 ng/ml per year 2
  years ? refer to urologist