Men’s Health – Pathophysiology
Adult-Onset Male Hypogonadism
- Clinical syndrome resulting from failure to produce testosterone OR failure to make normal
amounts of sperm OR both
- Clinical and biochemical syndrome characterized by a unequivocally and consistent (>1 test)
deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or
hypothalamic-pituitary (HP) dysfunction
- Average 1% decline per year after 40 years old
o Obesity and other medical conditions can
increase this decline
Testestrone
- Diurnal rhythm (high in AM and HS, lower in the day)
- Older men have less pronounced diurnal rhythm
- DHT – most potent form of T
Causes of male hypogonadism
- Primary (testes)
o Advanced age, chemo, mumps, radiation, orchidectomy, orchitis, testicular trauma,
torsion, medications, ESRD
- Secondary (upstream)
o Hypothalamus/pituitary dysfunction or tumor, iron overload syndrome, medications,
obesity, organ failure
Testestrone levels
- As you age, both TT, FT go down, especially FT
- AGE RELATED DECLINE is both primary and secondary
o Pulsatile GnRH is weakened and therefore less LH/FSH, therefore less testestrone
o LH response is reduced due to pituitary gland not responding
o Testicular response to LH is impaired (probably due to declining androgen levels)
Hypothalamic-pituitary-gonadal HPG axis
- Primary (testes)
o Testestrone low
o LH/FSH levels high
o Fertility cannot be restored (seminiferous damage)
- Secondary (hypo/pituitary)
o Testestrone low
o LH/FSH normal or low
o Fertility can be restored using pulse GnRH
,Signs and symptoms
- Sexual: decreased libido, ED, decreased AM erection, decreased performance
- Somatic (takes 6-12 months): decreased body hair, decreased testicular volume, decreased
muscle mass, increase body fat and central obesity, gynecomastia, osteoporosis…etc.
- Psychological: depression, mood changes, irritability, concentration issues, sleep disturbances
Diagnosis
- When measuring tT, measure 7-11 or 3 hrs after waking
- consider repeating to confirm level
Measuring T
- 98% of circulating testosterone is bound to serum proteins
o ~44% strongly (irreversibly) bound to SHBG (not bioavailable)
o ~50% weakly (reversibly) bound to albumin (bioavailable)
o ~4% weakly (reversibly) bound to corticosteroid-binding globulin (bioavailable)
- ~2% unbound or free (bioavailable)
- SHBG levels increase with aging, therefore bioavailable concentrations decrease
Measuring free T
1. SHBG may be decreased
a. Conditions: Obesity, diabetes, hypothyr, nephrotic syndrome, polymorph in SHBG gene
b. Drugs: glucocorticoids, some progestins, androgenic steroids
2. SHBG may be increased
a. Conditions: Aging, HIV, Cirrhosis hepatitis, hyperthyr, polymorphisms in the SHBG gene
b. Drugs: Some anticonvulsants, estrogens
, 3. Total testosterone is borderline / low normal
Androgenetic Alopecia (Male pattern baldness)
- Vertex or anterior pattern or both
- Prevalence varies by age and race
o 30% of Caucasian men by age 30, and keeps increasing
o Less common in Asian and African men
Pathogenesis
- Androgens: Androgen-dependent trait that requires a genetic predisposition
- Genetics: Androgen receptor gene is located on the x chromosome
o Passed from mom to son but still high concordance b/w fathers and sons (RR of 5.5)
- Thinning starts in crown area and gradually progresses to the mid-scalp area
- Number of hair follicles and growth cycle remain constant
o But the anagen or growth stage is shorter (length of growth period is shorter)
Causes a shorter and thinner hair shaft
o Ratio of 12:1 (normal scalp) to less than 5:1 (AA) of anagen to telogen
- 5AR converts T to DHT, DHT acts on hair follicle
- Two isoforms of 5AR in scalp hair follicles
o Type 1 in sebaceous glands, epidermal and follicular keratinocytes, dermal papillae cells,
and sweat glands
o Type 2 in outer sheath of hair follicles (plus epididymis, vas deferens, seminal vesicles,
and prostate)
Key pathophysiology features
1. Alteration in hair cycle development: Anagen phase decreases with each cycle while telogen
phase remains the same length. Eventually the anagen phase becomes so short that hair does
not reach the surface of the skin.
2. Follicular minimization
3. Inflammation: Studies suggest that inflammation is a feature in MAA even though its
significance in the pathogenesis of the disease is controversial.
Benign Prostate Hyperplasia (BPH)
- Common cause of urinary dysfunction sx in elderly men & most common benign neoplasm in
men. FYI: hyperplasia = increase in number
- Peak in mid 60s, rare before 50s
- 80-90% of men will have evidence of BPH by age 80 & “all” will develop if they live long enough
BPH risk factors (mechanism poorly understood)
- High levels of endogenous T, DHT, Estradiol, insulin-like growth factor, & inflammation markers
(c-reaction protein), obesity, diabetes, high levels of alcohol consumptions, physical inactivity
Prostate
Adult-Onset Male Hypogonadism
- Clinical syndrome resulting from failure to produce testosterone OR failure to make normal
amounts of sperm OR both
- Clinical and biochemical syndrome characterized by a unequivocally and consistent (>1 test)
deficiency of testosterone (T) with symptoms and signs that can be caused by testicular and/or
hypothalamic-pituitary (HP) dysfunction
- Average 1% decline per year after 40 years old
o Obesity and other medical conditions can
increase this decline
Testestrone
- Diurnal rhythm (high in AM and HS, lower in the day)
- Older men have less pronounced diurnal rhythm
- DHT – most potent form of T
Causes of male hypogonadism
- Primary (testes)
o Advanced age, chemo, mumps, radiation, orchidectomy, orchitis, testicular trauma,
torsion, medications, ESRD
- Secondary (upstream)
o Hypothalamus/pituitary dysfunction or tumor, iron overload syndrome, medications,
obesity, organ failure
Testestrone levels
- As you age, both TT, FT go down, especially FT
- AGE RELATED DECLINE is both primary and secondary
o Pulsatile GnRH is weakened and therefore less LH/FSH, therefore less testestrone
o LH response is reduced due to pituitary gland not responding
o Testicular response to LH is impaired (probably due to declining androgen levels)
Hypothalamic-pituitary-gonadal HPG axis
- Primary (testes)
o Testestrone low
o LH/FSH levels high
o Fertility cannot be restored (seminiferous damage)
- Secondary (hypo/pituitary)
o Testestrone low
o LH/FSH normal or low
o Fertility can be restored using pulse GnRH
,Signs and symptoms
- Sexual: decreased libido, ED, decreased AM erection, decreased performance
- Somatic (takes 6-12 months): decreased body hair, decreased testicular volume, decreased
muscle mass, increase body fat and central obesity, gynecomastia, osteoporosis…etc.
- Psychological: depression, mood changes, irritability, concentration issues, sleep disturbances
Diagnosis
- When measuring tT, measure 7-11 or 3 hrs after waking
- consider repeating to confirm level
Measuring T
- 98% of circulating testosterone is bound to serum proteins
o ~44% strongly (irreversibly) bound to SHBG (not bioavailable)
o ~50% weakly (reversibly) bound to albumin (bioavailable)
o ~4% weakly (reversibly) bound to corticosteroid-binding globulin (bioavailable)
- ~2% unbound or free (bioavailable)
- SHBG levels increase with aging, therefore bioavailable concentrations decrease
Measuring free T
1. SHBG may be decreased
a. Conditions: Obesity, diabetes, hypothyr, nephrotic syndrome, polymorph in SHBG gene
b. Drugs: glucocorticoids, some progestins, androgenic steroids
2. SHBG may be increased
a. Conditions: Aging, HIV, Cirrhosis hepatitis, hyperthyr, polymorphisms in the SHBG gene
b. Drugs: Some anticonvulsants, estrogens
, 3. Total testosterone is borderline / low normal
Androgenetic Alopecia (Male pattern baldness)
- Vertex or anterior pattern or both
- Prevalence varies by age and race
o 30% of Caucasian men by age 30, and keeps increasing
o Less common in Asian and African men
Pathogenesis
- Androgens: Androgen-dependent trait that requires a genetic predisposition
- Genetics: Androgen receptor gene is located on the x chromosome
o Passed from mom to son but still high concordance b/w fathers and sons (RR of 5.5)
- Thinning starts in crown area and gradually progresses to the mid-scalp area
- Number of hair follicles and growth cycle remain constant
o But the anagen or growth stage is shorter (length of growth period is shorter)
Causes a shorter and thinner hair shaft
o Ratio of 12:1 (normal scalp) to less than 5:1 (AA) of anagen to telogen
- 5AR converts T to DHT, DHT acts on hair follicle
- Two isoforms of 5AR in scalp hair follicles
o Type 1 in sebaceous glands, epidermal and follicular keratinocytes, dermal papillae cells,
and sweat glands
o Type 2 in outer sheath of hair follicles (plus epididymis, vas deferens, seminal vesicles,
and prostate)
Key pathophysiology features
1. Alteration in hair cycle development: Anagen phase decreases with each cycle while telogen
phase remains the same length. Eventually the anagen phase becomes so short that hair does
not reach the surface of the skin.
2. Follicular minimization
3. Inflammation: Studies suggest that inflammation is a feature in MAA even though its
significance in the pathogenesis of the disease is controversial.
Benign Prostate Hyperplasia (BPH)
- Common cause of urinary dysfunction sx in elderly men & most common benign neoplasm in
men. FYI: hyperplasia = increase in number
- Peak in mid 60s, rare before 50s
- 80-90% of men will have evidence of BPH by age 80 & “all” will develop if they live long enough
BPH risk factors (mechanism poorly understood)
- High levels of endogenous T, DHT, Estradiol, insulin-like growth factor, & inflammation markers
(c-reaction protein), obesity, diabetes, high levels of alcohol consumptions, physical inactivity
Prostate
