Male Reproduction:
Learning Objectives
1. How are requirements and timing for meiosis
different in males compared to females?
2. What events are required for formation of
sperm? What roles do hormones and
accessory cells play? What are normal sperm
counts and how long does it take to affect sperm
numbers?
3. What structures and glands are required for
sperm to exit the body?
4. How might novel methods of male contraception
take advantage of these required events and
structures?
Current Male Contraceptives
•
1.
2.
3.
•
1.
Three methods currently available:
Withdrawal: 27% pregnancy rate/year
Vasectomy: permanent sterilization
Condoms: great for preventing STDs
Do we need more?
Persistently high teen pregnancy rate,
abortions, dissatisfaction with choices.
2. 1/7 women worldwide die in childbirth, aid to
developing countries can only provide about
1 condom/man per year.
Clicker Question 1
•
Would you use a new method of
contraception for men or encourage your
partner to use one?
1. Yes
2. No
Methods in Development
1. Affect formation of sperm
2. Affect ability of sperm to exit the
body
3. Affect the ability of sperm to
fertilize an egg.
Type 1: Formation of Sperm
Meiosis in testis, external in mammals
Scrotum creates heat exchange to lower
temperature to below 95°F.
Type 1: Formation of Sperm
Heat Methods of Contraception
Protein Heat Shock Factor initiates cell death in
sperm over 95°F
1. Simple wet heat: 1946 Dr. M. Voegeli reported
10 years of experiments on 9 male volunteers
that showed method was effective and
reversible.
“Sits in a shallow or testes-only bath of 116°F
for 45 minutes daily for 3 weeks.
Six months of sterility results, after which
normal fertility returns.”
Type 1: Formation of Sperm
How Hot is 116°F?
Temperature
Typical Usage
Sensation
120°F
Recommended home
faucet temp
Burn in 10
minutes
Pain threshold
for adults
116°F
Testes-only bath
110°F
Hot shower
Very hot but not
painful
Very warm
105°F
Maximum tolerable
bath temp
Hot tub temp
118°F
101°F
warm
warm
Type 1: Formation of Sperm
Heat Methods of Contraception
Protein Heat Shock Factor initiates cell death in
sperm over 95°F
2. Artificial cryptochordism/suspensories: John
Rock and Derek Robinson of Harvard built on
Voegeli’s work in the 1960s to investigate
insulated underwear. Two pieces of evidence,
heat effects and the fact that men with
undescended testis (cryptochordid) were often
infertile. Method: keep the testes close to the
inguinal canal (the tube into which retractile
testes withdraw) during waking hours.
Type 1: Formation of Sperm
Suspensories
Publication
1987
Average sperm
count
12 million/ml
Average
motility
22-30%
1991
3 million/ml
15%
1997
<2 million/ml
Method
briefs
Rubber ring
Type 1: Formation of Sperm
Clicker Question 2
•
A.
B.
C.
D.
E.
How many sperm are normally present in
a milliliter (1/5 tsp)of semen?
100,000
1 million
10 million
50 million
100 million
Type 1: Formation of Sperm
Clicker Question 3
•
•
A.
B.
C.
D.
Still sounds like plenty of sperm!
No, men are often diagnosed with
infertility with sperm counts as low as:
15 million sperm/ml
20 million sperm/ml
40 million sperm/ml
50 million sperm/ml
Type 1: Formation of Sperm
• The following figure shows the process of meiosis in the
seminiferous tubules in the male testis. Annotate the figure to
indicate names for the sperm precursor cells (spermatogonium,
primary and secondary spermatocytes, spermatids, and immature
sperm) and write the names for the type of division that the arrows
are indicating (mitosis, meiosis I, and meiosis II).
Type 1: Formation of Sperm
Type 1: Formation of Sperm
Typical Test Question 4
A.
B.
C.
D.
E.
Which choice is true about both sperm and
ova production?
Initiation of meiosis is continuous after
puberty.
Millions of mature gametes are produced
daily.
All resulting gametes are the same size.
All resulting gametes are haploid.
All cells that result from meiosis will function
as gametes.
Type 1: Formation of Sperm
How long would heat take?
•
Should take 2-2.5 months to become
effective.
• Reversible after 12-18 months.
• Concerns:
1. Potential cancer risk: permanent natural
cryptorchidism since childhood is
associated with increase risk of testicular
cancer
2. Sperm DNA damage even after cessation?
Type 1: Formation of Sperm
How’d you know it’s working?
• $44.95 for two tests, 15
minutes
• Works by staining the cells in
the sperm sample to produce
a color, intensity then
compared to color reference
to determine if above or
below 20 million sperm/ml
Type 1: Formation of Sperm
Hormonal Contraceptives
Three Major Classes:
1. Androgens
2. GnRH antagonist
with androgen
replacement
3. Progestin with
androgen
replacement
Type 1: Formation of Sperm
Typical Test Question 5
•
A.
B.
C.
D.
Androgens, like testosterone can effectively reduce
sperm production because they act to lower production
of GnRH by the hypothalamus and LH by the pituitary.
This effectively prevents sperm production because
LH is needed to stimulate Leydig cells to make
adequate amounts of testosterone needed to stimulate
spermatogenesis in the testis.
LH is needed to stimulate Sertoli cells that are required
to nuture maturation of spermatids.
LH normally boosts to GnRH levels, so without LH,
there will not be enough GnRH to stimulate sperm
production.
LH boosts the production of inhibin which normally
lowers sperm counts.
Type 1: Formation of Sperm
Status of male pill
• Nothing available right now, may reach
European market in 10 years.
• Problems:
– Take 11/2 - 21/2 months to start.
– Progestins most well researched, good delivery,
therapeutic dose extremely narrow.
– Some of the androgens are only effective if injected
into muscle, working for time release.
– TE (10 days, but 100% reduction, Testosterone
buciclate (3 months, but only 40% reduction)
• Side effects of depressing “good” HDL cholesterol.
• Reversible in 3-5 months
• Non-response rates: 5-20%
Type 1: Formation of Sperm
Testis: full of Seminiferous Tubules
• Hollow tubes coiling through testis.
• Location of the divisions of meiosis.
• Location of cells needed to produce
testosterone, Leydig cells
Sertoli cells
nurture
developing
sperm cells
Type 1: Formation of Sperm
Adjudin: Sertoli Cells
• Derived from anti-cancer medication,
Lonidamine
• Changes sertoli cell connection to developing
spermatids so they break down before
maturation is complete.
• Problems:
– Delivery difficult, so attaching it to altered, nonfunctional FSH. FSH only binds to sertoli cells.
– Still has to be injected.
– Only tested in rats so far
Type 2: Sperm Exit
Type 2: Sperm Exit
Typical Test Question 6
A.
B.
C.
D.
E.
A man who was diagnosed with a very low sperm count was
given an vasograph (dye was placed in his reproductive tract)
and X-rays revealed the location of a blockage in his vas
deferens. What would this mean?
sperm are formed and mature normally, but they are blocked
from exiting the body and build up in the epididymis.
sperm cannot form because the cells that manufacture
testosterone in the vas deferens are prevented from functioning.
sperm are made normally but cannot reach the vas deferens
where they complete the final steps in maturation.
sperm cannot form normally because the blockage in the vas
deferens prevents the products of meiosis, the spermatids, from
reaching the epididymis where the must finish maturation.
this man can never have children because sperm form in the vas
deferens, and this blockage prevents the steps of meiosis from
occurring.
Type 2: Sperm Exit
Current Methods
1. Vasectomy (expensive to reverse, granulomas
(10%) and autoimmune response)
2. RISUG: (Reversible Inhibition of Sperm Under
Guidance) injected powdered styrene maleic
anhydride forms partial plug which can be later
flushed out. Phase III clinical trials India.
3. Injected plugs (clinical trial in 12,000 Chinese
men, 30-minute outpatient procedure, takes 12-18
months to work, epididymis rupture
4. Intra vas device (phase II clinical trials, China,
here in US by 2010, $1000
Type 2: Sperm Exit
Block Semen
Exit
• Dry Orgasm
• Phenoxybenzamine (blood pressure) /Thioridazine:
2006, block smooth muscle contractions in
reproductive tract.
– Seminal Vesicles: fructose (energy)
prostaglandins, basic fluids
– Prostate: enzymes, antibiotic
– Bulbourethral gland: mucus
Type 3: Block Fertilization
• Nifedipine, hypertension/migraine medicine
discovered in 1992 to cause infertility,
apparently through damage to sperm cell
membrane (lacked egg binding sugar and
had too much cholesterol in membrane. No
clinical trials, patents expired.
• Sperm enzyme inhibitors, 90% effective
when dissolved in rats drinking water.
Clicker Question 7
•
1.
2.
3.
4.
5.
6.
7.
8.
Which of the methods mentioned could you
see yourself (or your spouse using) in the
future?
Wet heat
Suspensories
Male Pill
Adjuvin (anti sperm maturation)
RISUG (reversible block in vas deferens
Smooth muscle contraction inhibitors
Sperm incapacitators
None of the above