Aging of Prostate

The Aging of the Prostate
Joyce C. Leary
April 23, 2001
The Aging of the Prostate:

Review
of the male reproductive system

What is the prostate and why do we care?
Pathology of the prostate:
Prostatitis
Benign Prostatic Hypertrophy (BPH)
Prostate Cancer
Main Components of the Male

Reproductive System:
Penis
contains urethra through which semen

and urine leave the body.
Testis production of sperm and hormones.
Epididymus, ejaculatory duct and vas deferens
tubing between testis and urethra.
Seminal vesicles, bulbourethral glands
(Cowpers), and prostate create seminal fluid.
The primary sex organ of the male is the testis.
From Wheaters Functional Histology, 4th ed. 2000
Hormonal regulation of Testis:
GnRH from hypothalamus stimulates anterior pituitary to

release LH and FSH.
LH (leutinizing hormone) stimulates Leydig cells to
produce testosterone and other androgens.
FSH (follicle stimulating hormone) maintains
spermatogenesis by stimulating Sertoli cells to produce
androgen-binding protein and inhibin.
Testosterone stimulates spermatogenesis.
Testosterone and inhibin negatively feed back to
hypothalamus and inhibits GnRH secretion.
Testicular function is continuous, not cyclical.
Major actions of androgens/testosterone:

1)
2)
3)
Development and maintenance of male

secondary sex characteristics.
Growth-promotion; testosterone is an anabolic
steroid.
Negative feedback inhibition on hypothalamic
GnRH release.
Castration leads to increased levels of LH and FSH

secretion from the anterior pituitary.
Taking testosterone will decrease LH secretion and
reduce sperm count.
Age-related Reproductive Hormonal

Changes:
Decrease in:
Increase in:
Mean serum testosterone

aromatization
Clearance/production of testosterone
FSH concentration
Androstenedione/DHEA
estrogens
Bioactive LH
Mean LH response to GnRH
LH amplitude and/or frequency (altered pulse generation)
Inhibin concentration
-Normal or slight increase in sex hormone binding globulin

-Normal or slightly increased LH concentration
What is the prostate?

A gland
about the size of a walnut that

surrounds the urethra just proximal to the
penis.
A connective tissue capsule surrounds
glandular and stromal (smooth muscle and
connective tissue) components.
Glands are composed of branched channels
with alveoli (tubuloalveolar), and are arranged
concentrically around the urethra.
What does the prostate do?

Secretes a slightly alkaline fluid which increases sperm
motility and aids in fertilization by neutralizing acidic
secretions of the vas deferens and vagina.
Prostatic secretions include:
Zinc
Citric acid
Prostaglandins
Acid phosphatase
Prostate specific antigen (PSA)
Other proteases involved in the liquifaction of
semen.
anterior/superior
Anatomy of the Prostate:

U = prostatic urethra
St = fibrous stroma
ED = ejaculatory ducts
Sp = fibrous septa
TZ = transition zone
CZ = central zone
PZ = peripheral zone
C = urethral crest
posterior/inferior
From Wheaters Functional Histology, 4th ed., 2000.
Normal Histology
of the Prostate:
Branching glands (G) are
irregularly shaped to allow
distention of the glands by
collecting secretions.
The stroma (arrow) is dense
collagen, fibroblasts, and
sympathetically innervated
smooth muscle that contracts
during ejaculation.
In a normal prostate, the secretory glands exhibit doublelayered epithelium.
The Prostate and Testosterone:

The healthy prostate is an androgen-dependent
organits growth depends on the presence of
testosterone.
In the prostate, testosterone is converted to
dihydrotestosterone (DHT) by 5-alphareductase.
DHT stimulates growth of the prostate.
Normal aging of the prostate:

After
age 40:
Outer regions:
Atrophy
of smooth muscle and proliferation of connective
tissue
Flattening of secretory epithelium
Inner region:
Hyperplasia
After
age 60:
Slower, but more uniform atrophy of entire prostate

Accumulation of prostatic concretions
Physiological Basis of Aging and Geriatrics, 2 nd ed., 1998. Timiras.
Benign Prostatic Hyperplasia (BPH)
Caused by growth of the prostate from about age 40 to

death.
Affects 50% of men > 50 years old; affects 95% of men
> 70 years old.
BUT, clinical symptoms due to obstruction of the
urethra are present in only 5-10% of men with BPH.
Not cancer.
BPH tissue resembles normal prostate tissue with
increased amounts of smooth muscle, glandular,
and/or stromal components.
An enlarged prostate can strangle the urethra.
A patient may exhibit any

combination of BPH symptoms:
Increased frequency of urination, especially nocturia

(urination at night).
Some difficulty starting and stopping urination.
Urine stream that is weak and thin.
Dribbling after urination.
Urgent feeling of need for urination.
Feeling that bladder has not emptied completely.
Urinary retention (inability to urinate).
Hematuria (blood in the urine).
2 groups of men are impervious to

BPH:
1)
2)
Men who have been castrated.

Men with 5-alpha-reductase deficiency.
Thus, the presence of DHT has been shown to

induce hyperplasia in prostate cells via the
stimulation of growth factors.
Although men produce less testosterone with
age, they continue to produce DHT in the
prostate.
Risk factors for BPH:

Aging
Use
of anabolic steroids
No other major risk factors
Having BPH does not increase a mans risk for
developing prostate cancer. However, the
diseases often occur together.
BPH treatments:
Medications:
Antihypertensives (alpha-adrenergic blockers) to

relax the smooth muscle in and around the urethra.
May affect blood pressure.
Prostate-selective alpha-adrenoreceptor agonist
also relaxes smooth muscle around urethra. Does
not affect blood pressure.
5-alpha reductase inhibitors inhibit production of
DHT.
Bladder
Surgery
catheterization
Cross-section through prostate.

Hyperplastic Nodules. Arrow: urethra.
From the Interactive Case Study Companion to Robbins 6th Edition Pathologic Basis of Disease
Prostate Cancer Statistics:

184,000
new cases in U.S. in 1998.

A leading cause of cancer death in men, 2 nd
only to lung cancer.
Affects 82/100,000 men aged 50-54.
Affects 1326/100,000 men aged 70-74.
Mortality rates vary widely, especially across
ethnic groups.
5-year overall survival rates:

75%
African Americans
90% Caucasians
Diagnosis of Prostate Cancer:
Digital Rectal Exam
Physician feels prostate through wall of rectum to determine

hardness or lumps.
Can only identify tumors that are big enough to feel.
Measurement of PSA (prostate-specific antigen) in the

blood.
PSA is secreted by normal and cancerous prostatic cells, and

the levels of circulating PSA often rise with prostate cancer.
Thus, PSA levels can serve as a warning that the prostate
gland has gone awry.
Misses as many as 25% of men with cancer and misdiagnoses
many others.
More on Diagnosis:
Biopsy to determine morphological change of prostatic

cells via histologic assessment.
The Gleason scoring system, the single most important
prognostic factor for long-term survival, is used to rate
the aggressivity of the cancer--the level of
disorganization and the speed of growth:
Scale of 2-10 where lower scores indicate less aggressive,

more normally differentiated prostatic cells.
A higher Gleason score usually means that the tumor is fastgrowing and may have already metastasized.
Imaging: CT, transrectal ultrasound, MRI
High Power. Light arrows: Carcinomous prostate glands.

Dark arrow: Desmoplastic stroma.
Theorized risk factors for and/or causes

of prostate cancer:
Exposure to mutagens.
Exposure to mutagens and testosterone, combined.
Cadmium exposure.
Genetic predisposition/ familial predisposition/ race
High consumption of animal fat
Vitamin A deficiency
Possibly vasectomy
Sexually transmitted disease
Tobacco exposure
Sexual activity
Other mutagenic hormonal factors
Characteristics of Prostate Cancer:

Chromosomal
Deletions or mutations in chromosomal segments

Tumor suppressor gene alterations
Loss
of p53 or RB function linked to cancer development.
Variable length of the CAG repeat in hAR gene

hAR
abnormalities:
= human androgen receptor
Loss or methylation of promoter regions
Telomerase:
no correlation has been found

between the level of telomerase activity and
Gleason score or PSA level.
Other factors influencing

proliferation and progression:
Growth
factors
Mitosis promotion and anti-apoptosis effects
Adhesion
molecules
Loss of cadherin and integrins (less cell-to-cell

interaction.)
Helps tumor to escape the confines of the prostate
Proteases
Cancer cell acquired activity of metalloproteinases

(MMPs) that dissolve extracellular matrix and
promote metastasis.
Prostate Cancer Treatments:
Surgery best results for long-term survival if confined

prostate cancer.
Radiation best results for long-term survival if cancer is not

confined to the prostate.
Partial or Radical Prostatectomy

Cryosurgery
External Beam
Brachytherapy (radioactive pellet seeding)
Hormonal Therapy to block or stop production of

androgens in the prostate.
Antiandrogenic progestins
GnRH antagonists
Estrogen administration
Metastatic prostate cancer in vertebrae.

References:
Understanding Prostate Disease. 1999. Inlander, Norwood.

Peoples Medical Society.
Basic Histology 9th ed. 1998. Junqueira, Caneiro, Kelley.
Appleton & Lange.
Atlas of Functional Histology. 1998. Kerr. Mosby.
Physiology. 1998. Costanzo. Saunders Text and Review Series.
Combating Prostate Cancer. Garnick, Fair. Scientific American.
Dec 1998. p74-83.
Molecular Biology of Prostate Carcinogenesis. 1999. Lara Jr,
Kung, Gumerlock, Meyers. Oncology Hematology. Vol.32, 197208.
Physiological Basis of Aging and Geriatrics, 2nd ed., 1998.
Timiras, editor.
More references
Lepor, H. Prostatic Diseases. W.B. Saunders Co., 2000.

Young B, Heath JW: Wheaters Functional Histology, 4th ed. Churchill
Livingstone, 2000.
Isaacs JT, Coffey DS. Etiology and disease process of benign prostatic
hyperplasia. Prostate suppl 2:33-50, 1989.
White JW. The results of double castration in hypertrophy of the
prostate. Ann Surg 22:1-80, 1895.
Walsh, PC. Treatment of Benign Prostatic Hyperplasia. NEJM. August,
22, 1996: 586-587.
Taplin, ME, et al. Mutation of the androgen receptor gene in metastatic
androgen-independent prostate cancer. NEJM. 332: 1393-1398. 1995.
And more

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The Aging of the Prostate

The Aging of the Prostate:

of the male reproductive system

Main Components of the Male

contains urethra through which semen

From Wheaters Functional Histology, 4th ed. 2000

Hormonal regulation of Testis:

GnRH from hypothalamus stimulates anterior pituitary to

Testicular function is continuous, not cyclical.

Major actions of androgens/testosterone:

Development and maintenance of male

Castration leads to increased levels of LH and FSH

Age-related Reproductive Hormonal

Mean serum testosterone

-Normal or slight increase in sex hormone binding globulin

What is the prostate?

about the size of a walnut that

What does the prostate do?

Anatomy of the Prostate:

From Wheaters Functional Histology, 4th ed., 2000.

In a normal prostate, the secretory glands exhibit doublelayered epithelium.

The Prostate and Testosterone:

Normal aging of the prostate:

of smooth muscle and proliferation of connective

Slower, but more uniform atrophy of entire prostate

Physiological Basis of Aging and Geriatrics, 2 nd ed., 1998. Timiras.

Benign Prostatic Hyperplasia (BPH)

Caused by growth of the prostate from about age 40 to

A patient may exhibit any

Increased frequency of urination, especially nocturia

2 groups of men are impervious to

Men who have been castrated.

Thus, the presence of DHT has been shown to

Risk factors for BPH:

Antihypertensives (alpha-adrenergic blockers) to

Cross-section through prostate.

Prostate Cancer Statistics:

new cases in U.S. in 1998.

5-year overall survival rates:

Diagnosis of Prostate Cancer:

Digital Rectal Exam

Physician feels prostate through wall of rectum to determine

Measurement of PSA (prostate-specific antigen) in the

PSA is secreted by normal and cancerous prostatic cells, and

Biopsy to determine morphological change of prostatic

Scale of 2-10 where lower scores indicate less aggressive,

Imaging: CT, transrectal ultrasound, MRI

High Power. Light arrows: Carcinomous prostate glands.

Theorized risk factors for and/or causes

Characteristics of Prostate Cancer:

Deletions or mutations in chromosomal segments

of p53 or RB function linked to cancer development.

Variable length of the CAG repeat in hAR gene

= human androgen receptor

Loss or methylation of promoter regions

no correlation has been found

Other factors influencing

Mitosis promotion and anti-apoptosis effects

Loss of cadherin and integrins (less cell-to-cell