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Local and systemic control of gonadal function
Human: 1 oocyte – 150 million sperm
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VISIT NUMBER
CO
NC
EN
TR
AT
ION
1990199119921993
Semen analysis results vary considerablyeven in the normal fertile population.
CONSECUTIVE SEMEN DONORCONCENTRATIONS OVERFOUR YEARS
Cooper T G et al. Hum. Reprod. Update 2010;16:231-245
© World Health Organization [2009]. All rights reserved. The World Health Oragnization has granted Oxford University Press permission for the reproduction of this article
The association of age and semen quality in healthy men B.Eskenazi Human Reproduction Vol.18, pp. 447-454, 2003
Semen volume
Concentration
Count
Motility
Progressive motility
20 40 60 80 20 40 60 80
The likelihood of semen sample being graded as “clinically” abnormal or
unhealthy:
Age22 25%30 40%40 60%60 85%
So where are we going now?
So many sperm? Why? How?Environmental pollutants and male fertility?
3. Cervical mucus.a) penetration characteristicsb) “filter” for immotile sperm1. Human: Vaginal
deposition of semen
2. Human: 99% of sperm lost through retrograde transport
150,000,000
3. Cervical mucus.a) penetration characteristicsb) “filter” for immotile sperm1. Human: Vaginal
deposition of semen
2. Human: 99% of sperm lost through retrograde transport
4. Transport through uterus; phagocytosis
150,000,000
Dog sperm in contact with uterine epithelial cells
Courtesy: Gary England
3. Cervical mucus.a) penetration characteristicsb) “filter” for immotile sperm1. Human: Vaginal
deposition of semen
2. Human: 99% of sperm of sperm lost through retrograde transport
4. Transport through uterus due to muscular contractions; phagocytosis
5. Utero-tubal junction
6. Fallopian tube
150,000,000
The journey?
2. Human: 99% of sperm of sperm lost through retrograde transport
5. Utero-tubal junction
6. Fallopian tube
Sperm bound to ciliated epithelial cells – slow release
Spermatogenesis: How much do you need?
Body weight: 44 kg
Testis size: 120 gm
Body weight: 170 kg
Testis size: 30 gm
Many males mate with same female:
competition!
i.e. 16 x more testicular tissue/kg body wt
Take home message: the more testicular tissue, the more sperm.
Body weight
Tes
tis
wei
ght Man
Multi-male breeding system
Monogamous
~ 8 cm
Why so many sperm?
50 um/sec = 3 mm/min = ~30 min
Take home message: variability in reproduction often correlates withcompetition between males/sperm
Stahlberg et al (2000) pig experiment
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Boar A Boar B
Number ofembryos
% Siredoffspring
• Semen from 2 boars was pooled in equal numbers and inseminated (32 females)
• DNA analysis was used to identify paternity of offspring and embryos
Theriogenology (2000) 53, 1365-1373.Take home message: there is competition between sperm!
What controls testicular size/ sperm production?
Each Sertoli cell has a fixed capacity for the number of germ cells that it can support.
Therefore, the number of Sertoli cells in the adult testis determines (testis size) daily sperm production.
Sharpe, Reproduction(2003) 125, 769–784
The distribution profile of Sertoli cell number in a population of men: i.e. it is very variable
Sertoli cell number
Final terminal differentiation – losing ability to divide, but switching on spermatogenic support functionHypothesis:
Disturbances in testicular development will affect male fertility.
Proliferation during fetal and neonatal life
Proliferationperipubertally.
Testis
Spermatozoa
Hypothalamus
Pituitary
FSH LH
++
GnRH+
Testosterone
Negative feedback
Inhibin
The “TEXT BOOK” control of the testis and spermatogenesis
Testis
Spermatozoa
Hypothalamus
Pituitary
FSH LH
++
GnRH+
Testosterone
Suppress FSH/LH
GnRH antagonist?
Increase feedback:Give testosterone
Negative feedback
Observation: The 1st large scale trials in 1990s - highly effective in reducing sperm counts in most men, BUT a small % of men failed to show sufficient suppression of sperm – even when gonadotrophin levels were undetectable.
Observation: The 1st large scale trials in 1990s - highly effective in reducing sperm counts in most men, BUT a small % of men failed to show sufficient suppression of sperm – even when gonadotrophin levels were undetectable.
The difficulty of getting a male contraceptive..
Normal testes
“wild type”
Small testes, but still fertile
But in the FSH “knockout”
Conclusion: FSH is NOT essential for spermatogenesis…
Conclusion: FSH is NOT essential for spermatogenesis…
For many years, FSH had been seen as the main driving force in spermatogenesis…
FSH
Sertoli cells
FSH receptors
Is the same true for man?
Yes - very similar!
Men with an inactivating mutation of the FSH receptor are fertile despite having small testes.
Conclusion:
FSH is not essential for spermatogenesis…
– but does seem to be important in determining testicular size
No Spermatozoa
Hypothalamus
Pituitary
FSH LH
++
GnRH+
Testosterone
Prepubertal boys
Negative feedback
Small testes
Spermatozoa
Hypothalamus
Pituitary
FSH LH
++
GnRH+
Testosterone
Prepubertal boys
Negative feedback
Small testes
Spermatogenesis can Spermatogenesis can occur in testes with occur in testes with Leydig cell tumours in Leydig cell tumours in pre-pubertal pre-pubertal boysboys
Spermatogenesis can Spermatogenesis can occur in testes with occur in testes with Leydig cell tumours in Leydig cell tumours in pre-pubertal pre-pubertal boysboys
Perhaps local Perhaps local steroids may be steroids may be important in important in spermatogenesis?spermatogenesis?
TESTOSTERONE
Perhaps this explains the small % of men who failed to show sufficient suppression of sperm – even when gonadotrophin levels were undetectable – in the contraceptive trials
Perhaps this explains the small % of men who failed to show sufficient suppression of sperm – even when gonadotrophin levels were undetectable – in the contraceptive trials
Intra-Testicular Circulation
T 1500 25 nmol/L
E2 11000 27 pmol/L
Local steroids may be important in Local steroids may be important in spermatogenesis?spermatogenesis?
Are local steroids Are local steroids really important?really important?
Are local steroids Are local steroids really important?really important?
Leydig cellsSertoli cells
Peritubular cells
AR
AR null
AR
AR
Location of androgen receptors
Androgen receptor knockout (AR null)
WT
Direct evidence that testosterone acting via Sertoli cells is important for later stages of spermatogenesis.
Where are the steroids acting?
Where are the steroids acting?
Small testes
AR-null
Leydig cellsSertoli cells
Peritubular cells
Androgen receptor knock-out in Sertoli cells only
AR
AR
AR
Result: Spermatogenesis becomes arrested during meiosis
Testosterone
↑↑ later stages of spermatogenesis
FSH
↑ Leydig cell no.
↑↑ early Sertoli cell proliferation
↑↑ later Sertoli cell proliferation Initiates spermatogenesis↑↑ Spermatogonia no.
LH
AR
AR
Conclusion:
Sequential, coordinated
actions of LH, FSH and
androgens are required.
Conclusion:
Sequential, coordinated
actions of LH, FSH and
androgens are required.
Leydig cell development
Peri-tubular cells
By end of 1st year, few Leydig
cells left
2nd wave of Leydig cells (peaks at 3
mo ) + T surge
1st wave of Leydig cells. T production stimulated by
hCG
Adult Leydig cells differentiate from undifferentiated
precursors
Sertoli cell number
Leydig cells
Men: 100-200 m sperm each day
Men: 100-200 m sperm each day
The no. of sperm determined by no. of Sertoli cells.
The no. of sperm determined by no. of Sertoli cells.
Sperm count (106/ml)
Sperm count (106/ejaculate)
Daily sperm production (106/testis)
% m
en
% b
ecom
ing
pre
gnan
t p
er c
ycle
. Sertoli cell number/testis (m)
FertilityFertility
The number of Sertoli cells is fixed by puberty.
Largely determined by rate of proliferation in fetus and 1-9 months post-natal.
The number of Sertoli cells is fixed by puberty.
Largely determined by rate of proliferation in fetus and 1-9 months post-natal.
Therefore, factors affecting no. of Sertoli cells in early life will
influence sperm counts in adulthood.
Therefore, factors affecting no. of Sertoli cells in early life will
influence sperm counts in adulthood.
The sperm count in men varies. Normally, 100-200 m sperm each day
The sperm count in men varies. Normally, 100-200 m sperm each day
If sperm count is too low, fertility
declines
If sperm count is too low, fertility
declines
FSH Testosterone from fetal Leydig cells
Endocrine disrupting compounds