Andropause testosterone therapy in elderly male

1. “Andropause" “Late-onset
hypogonadism.
Doha Rasheedy
Assistant Professor
Geriatrics and Gerontology Department
Faculty of Medicine
Ain Shams University

2. • Hypogonadism in older men is a syndrome
characterized by low serum testosterone
levels and Specific clinical symptoms.
• These symptoms include decreased libido,
erectile dysfunction, decreased vitality,
decreased muscle mass, increased adiposity,
depressed mood, osteopenia, and
osteoporosis.

3. FREE / BIOAVAILABLE TESTOSTERONE

4. • Testosterone, which is the most plentiful androgen
in the human male, circulates in blood bound to
two proteins, albumin and sex hormone-binding
globulin (SHBG); only about 1% to 2% of
testosterone circulates totally free in plasma.
• Testosterone is tightly bound to SHBG, whereas its
affinity for albumin is weak.
• Because of the strong affinity of testosterone for
SHBG, the portion of plasma testosterone not
bound to SHBG is often called bioavailable
testosterone.

5. • Testosterone is actively metabolized to the estrogen,
estradiol (E2) and 5 α dihydrotestosterone (DHT), a
more potent androgen than testosterone, by the
enzymes aromatase and 5 α-reductase type 1 and 2,
respectively.
• Many testosterone actions are mediated, at least in
part, by its active metabolites, E2 (eg, on bone, brain,
and lipids) and DHT (eg, on prostate).
• Despite declining serum testosterone levels, total
E2 and DHT concentrations do not change (or else
decrease only slightly) with aging, suggesting:
– a relative increase in conversion of testosterone to E2 and
DHT,
– and/or
– reduction in the metabolic clearance of these active
metabolites.

6. CHANGES WITH AGE

7. Physiological changes due to Ageing
1.  total testosterone concentration
2. ↑ sex hormone binding concentration (SHBG)
3.     free testosterone to a greater degree than the
total testosterone.
4.    bioavailable testosterone
5. The circadian rhythm of both free and bioavailable
testosterone is blunted with age.
6. As men age, serum gonadotropin concentrations increase,
↑ ↑ FSH more than ↑ LH, but the rise is not so great as
one would expect from the fall in testosterone, suggesting
that the fall in testosterone with aging is due to both
secondary and primary hypogonadism.
7. ↔ Sperm production does not appear to change
dramatically with increasing age.

8. Physiological changes due to Ageing-
2
1.  Testicular volume of men older than 75 years is 31%
smaller than that of men aged 18 to 40 years (20.6 mL vs.
29.7 mL).
2.  Leydig cell number is approximately 44% lower in men
aged 50 to 76 years than in men aged 20 to 48 years

9. Confounding factors to low
testosterone in elderly
not all studies have observed lower testosterone levels in older men.
• Studies of healthy men describe no difference in testosterone
concentrations between older and younger men,suggesting that
ill health may contribute substantially to the apparent age-related
testosterone decline.
1. obesity plays a role in the fall in testosterone levels with aging. Despite
having lower testosterone concentrations than lean men, obese men do
not have elevated LH concentrations;
2. Chronic illness contributes also to the decline in testosterone levels with
aging, LH concentrations are not elevated in those with chronic
illness; this finding suggests a hypothalamic-pituitary defect.
3. Statin use and vitamin D deficiency have also been reported to be
associated with lower testosterone levels in older men.
4. Frailty is associated with lower free testosterone and higher LH,
suggesting activation of functional reserve in the HPG axis to
compensate for impaired testicular function

10. CLINICAL PICTURE

11. • None of these symptoms is unique to
hypogonadism e.g.
1. Sexual effects
2. Body composition
3. Metabolic profile
4. cognition

12. Sexual function
1. Erections: reduced quality and frequency,
including nocturnal erections
2. Oligospermia or azoospermia
3. Gynecomastia/breast discomfort
4. Changes in secondary hair characteristics
5. Changes in size of testes
6. Decreased fertility
7. Decreased lipido

13. Muscle, bone, and body composition
• Progressive decrease in muscle mass
• Increase in visceral fat
• Decrease in bone mineral density; osteopenia,
osteoporosis, increased risk of bone fractures
• Decreased physical function
• Slow gait speed

14. Metabolic
• Lipid abnormalities
• Impaired glucose tolerance
• Increased cardiovascular risks

15. others
1. Mild anemia (normochromic, normocytic)
2. Sleep disturbance
3. Depressed mood: testosterone therapy does appear
to have a positive impact on mood
4. Decreased energy
5. Cognitive Decline.
6. some studies have shown an association between
low testosterone levels with increased mortality
and some have not

16. LATE-ONSET HYPOGONADISM
• This syndrome affects approximately 3% of men
aged 60 to 69 years
• Defining late-onset hypogonadism (LOH) as:
1. the presence of three sexual symptoms:
1. decreased frequency of morning erection
2. decreased frequency of sexual thoughts
3. erectile dysfunction
2. total testosterone concentration less than 11
nmol/L
3. a free testosterone concentration less than
220 pmol/L

17. CAUSES

18. Types of hypogonadism
• primary or secondary hypogonadism caused by testicular or
hypothalamic-pituitary disorders, respectively.
Hypopituitarism can cause secondary hypogonadism:
• Causes include:
1. hypothalamic-pituitary tumor (e.g., prolactinoma or
nonfunctioning adenoma),
2. hypothalamicpituitary infiltration (e.g., hemochromatosis)
3. medications (e.g., glucocorticoids, opioid analgesics)
4. brain insult (e.g., traumatic injury, irradiation)
5. chronic illness (e.g., diabetes and HIV infection).

19. Risk factors for hypogonadism in older
men may include:
1. chronic illnesses including
– diabetes mellitus
– chronic obstructive lung disease
– inflammatory arthritic disease
– renal disease
– HIV-related disease
2. obesity, metabolic syndrome
3. hemochromatosis

20. • Primary Hypogonadism results from disorders of the testes that
lead to low testosterone production and impaired fertility. The
laboratory values for patients with primary hypogonadism show
low testosterone and elevated LH and FSH levels.
• Secondary hypogonadism results from disorders of the
hypothalamus and the pituitary. The laboratory values for men
with secondary hypogonadism show low testosterone and low or
inappropriately normal LH and FSH levels.
• Mixed hypogonadism can result from dual defects in the testes
and in the pituitary-hypothalamic axis. The laboratory values for
mixed hypogonadism can be varied including cases with low
testosterone with mild increases in LH and FSH levels.
• Often the type of hypogonadism in older men is either
secondary or mixed hypogonadism.

21. The decline in testosterone levels can be due to
several factors including
• (1) decline in Leydig cell function,
• (2) decline in pituitary-hypothalamic axis
function with loss of circadian variation
• (3) increase in the levels of SHBG,
• (4) changes in testosterone receptors sensitivity,
• (5) effects of altered cardiometabolic and
inflammatory markers

22. PREVALENCE OF HYPOGONADISM IN
ELDERLY
• In the Baltimore Longitudinal Study on Ageing,
it was found that 19% of men over 60 years
had low testosterone.

23. DIAGNOSTIC EVALUATION

24. • The Endocrine Society recommends that the diagnosis of
testosterone be made in men who have both consistent signs and
symptoms + low total testosterone levels.
1. Screening tools (The Androgen Deficiency in Ageing Males
(ADAM) questionnaire)
2. Morning fasting serum total testosterone <300 ng/ml (repeated
twice)
3. free testosterone or Bioavailable T measurements in all men
other than healthy lean young men (whose SHBG levels are
presumably normal and whose measured total testosterone
concentration is reliable).
4. The final step in determining whether a patient has primary or
secondary hypogonadism is measuring the serum LH and FSH.
5. serum prolactin is indicated when the serum testosterone is
lower than 5.2nmol/l (150ng/dl) or when secondary
hypogonadism is suspected

25. precautions
• Transient decreases of serum testosterone
levels such as those due to acute illnesses
should be excluded by careful clinical
evaluations and repeated hormone
measurement.

26. Results
• the total testosterone level above 12nmol/l
(350ng/dl) does not require substitution.
• patients with serum total testosterone levels
below 8nmol/l (230ng/dl) will usually benefit
from testosterone treatment
• a free testosterone level below 225pmol/l
(65pg/ml) can provide supportive evidence for
testosterone treatment
• Threshold values for bioavailable testosterone
depend on the method used and are not
generally available

27. Androgen deficiency in ageing males
(ADAM) questionnaire
1.Do you have a decrease in libido (sex drive)?
2.Do you have a lack of energy?
3.Do you have a decrease in strength and/or endurance?
4.Have you lost height?
5.Have you noticed a decreased enjoyment of life?
6.Are you sad and/or grumpy?
7.Are your erections less strong?
8.Have you noticed a recent deterioration in your ability to play sports?
9.Are you falling asleep after dinner?
10.Has there been a recent deterioration in your work performance?
• If the answer is ‘yes’ to question 1 or 7, or at least 3 of the other questions, low
testosterone may be present.
• not recommended for the diagnosis of hypogonadism because
of low specificity

28. Conditions requiring measurement of
serum testosterone
1. Infertility
2. Osteoporosis, low trauma fracture
3. Type 2 diabetes mellitus
4. Glucorticoid, ketoconazole, opioid or other
medications that affect T metabolism or production
5. Moderate to severe COPD
6. Sellar mass, radiation to the sellar region, or other
diseases of the sellar region
7. End-stage renal disease, maintenance haemodialysis
8. HIV-associated weight-loss

29. Conditions with high and low SHBG
levels
• Increased SHBG
concentrations
• Ageing
• Hepatic cirrhosis
• Use of anticonvulsants
• Use of estrogens
• Hyperthyroidism
• HIV infection
• Catabolic conditions
(malnutrition; malabsorption)
• Decreased SHBG
concentrations
• Use of glucocorticoids,
progestins, anabolic steroids
• Type 2 diabetes
• Nephrotic syndrome
• Hypothyroidism
• Obesity; metabolic syndrome

31. MANAGEMENT

32. • The question of whether or not testosterone
should be administered to older men is
difficult to answer.

33. Treat the cause
1. Dopamine agonist therapy will increase testosterone
levels in men with hyperprolactinemia
2. bariatric surgery for men with DM 2, severe obesity, or
both.
3. less severe obesity, diet and exercise increases
testosterone levels.
4. For men with a low testosterone level and non-elevated
LH levels (secondary hypogonadism) who desire fertility,
consideration should be given to antiestrogen, aromatase
inhibitor, gonadotropin therapy, and/or pulsatile
gonadotropin-releasing hormone therapy

34. TESTOSTERONE THERAPY

35. • use of testosterone therapy for men with
aging-related hypogonadism only if:
1. testosterone levels are confirmed to be low (2
consecutive measurements are required, early
morning, fasting samples)
2. the patient has features consistent with
hypogonadism
3. appropriate screening for disease of the HPG
axis is performed

36. FORMULATION

39. • Transdermal and buccal formulations of
testosterone therapy require daily administration
• testosterone gel users must consider the
possibility of contact with, and therefore
testosterone transfer to, a pregnant or breast-
feeding woman
• Intramuscular testosterone ester preparations are
given every 3 to 14 weeks.
• Oral testosterone and 17α-alkylated androgen
preparations are not recommended because of
potential liver toxicity and variable clinical
response, drug not in use, may adversely affect
lipid profile, decreasing HDL, and increasing LDL

40. Contraindications
• Male breast cancer
• Prostate cancer (known or suspected) PSA>3ng/dl
abnormal DRE
• Known or suspected sensitivity to ingredients used in the
testosterone delivery systems
Precautions
• Benign prostatic hyperplasia (BPH); lower urinary tract
symptoms (LUTS)
• Oedema in patients with preexisting cardiac, renal, or
hepatic disease
• Gynaecomastia
• Precipitation or worsening of sleep apnoea
• Azoospermia; testicular atrophy
• Erythrocytosis HCT>50
• Increase cardiovascular risks

41. Monitoring
• It is recommended to perform a baseline digital
rectal examinations (DRE) and a baseline PSA level
measurement before starting testosterone
therapy for any man, whatever his age , then
repeat every 6 months
• Serial HCT level stop if >54%

43. • The dose of testosterone therapy should be
titrated to maintain a predose testosterone
level in the middle to lower part of the normal
reference range.
• The target serum testosterone concentration
in these men should be lower than that for
younger men, for example, 300 to 400 ng/dL
(10.4 to 13.9 nmol/L), rather than 500 to 600
ng/dL (17.4 to 20.8 nmol/L),

44. Benefits of testosterone replacement
1. improves sexual interest, spontaneous erections, and, to a lesser extent,
erectile dysfunction in hypogonadal men
2. increased total lean body mass, lower limb muscle strength, and self-reported
physical function (SF-36) but did not improve significantly objective physical
function except in the subgroups comprising older (aged ≥75 years) and frailer
men (≥2 Fried frailty criteria
3. testosterone therapy has a positive impact on mood
4. increased lumbar spine, but not hip, BMD compared to placebo.Bone density
in hypogonadal men of all ages increases under testosterone substitution.
Fracture data are not yet available and thus the long-term benefit of
testosterone requires further investigation
5. no improvement in insulin resistance (as assessed by HOMA2-IR) or in
glycemic control
6. correction of anemia has not yet been demonstrated.

45. When to discontinue???
1. Failure to benefit clinical manifestations within a
reasonable time interval (3–6 months is
adequate for libido and sexual function, muscle
function, and improved body fat; improvement
in bone mineral density requires a longer interval
to show improvement) should result in
discontinuation of treatment. Further
investigation for other causes of symptoms is
then mandatory
2. Adverse effects: polycythemia, cancer prostate