This document discusses issues related to treating male infertility in the era of ICSI. It argues that while ICSI provides an effective technique for bypassing sperm dysfunction, solely relying on ICSI and not properly diagnosing and treating the underlying causes of infertility can amount to negligence. The document emphasizes that andrology inputs are still important to address general health issues, infections, obstructions, hypogonadism, and genetic factors that may be contributing to poor sperm production or quality. A complete diagnosis and treatment of the male is important even in the ICSI era to help address underlying pathology and implications for health and inheritance.

1. Do We Treat Male Infertility in the
Era of ICSI ?

Dr. Anand K. Shinde
M. D. (Gyn )
IVF Consultant
& Director of Andrology
At“IVF Pune”, 7th floor
Deenanath
Mangeshkar Hospital Pune-4
Tel : 40151777

3. Do We Treat Male Infertility in the Era
of ICSI ?

The Main Points of this presentation would be--

What is “Era of ICSI”

What is “ Treating the male factor ” ?

Is there any controversy ?

4. Male Factor Infertility

Barring coital difficulties or severe hypospadias or ejaculatory
dysfunctions, the “Male factor” in Infertility means poor
numbers or poor quality of Sperms.

The Topic of Male factor Infertility is vast. We can give only a
glimpse of it here.

Quality & number of Sperms produced by the testes is
determined mainly by the interaction of 3 factors-
1. Genetic make up of the Spermatogonia
2. Normal Sertoli and Leydig Cell function
3. The interaction of Sertoli, Leydig & Germ cells
with endogenous factors and the environment.

5. Male Factor Treatment

For “Male Factor” Treatment there can be two
strategies to optimize or “nurture” sperm production
and quality
1. Preproduction nurturing before ejaculation
2. Post production nurturing for preserving and
optimizing sperm quality and function after
ejaculation.

6. Male Factor Treatment Means
1 Interventions for better production
(numbers/qualities) of Sperm in fertile/
infertile male
2 Interventions called Assisted
reproductive techniques used to bypass
defects in Sperm function.

7. Treating the Male Factor

ICSI is one such 'Post Production' nurturing
technique, which is effective in certain male
factor.

First ICSI pregnancy was reported by
Palermo ( Lancet 1992)

So what does this ICSI era mean ?

8. Era of ICSI
ICSI – Impressive, Complete Solution to Infertility?
'For decades, various therapies have been proposed to
improve semen parameters in cases of male factor
infertility.
Administration of antiestrogens & androgen have been found
to be ineffective. No peer review data are available to
demonstrate the benefit of the use of IUI or correction of
varicocoele.
The conventional treatement for the male factor infertility
has little value and has been revised & abandoned.
ICSI has to be considered as the method of choice and
should replace ineffective conventional therapies (Devroey
P, 1998)

9. Era of ICSI

“There no longer seems to be any category of male factor infertility
that cannot be treated with ICSI. Even for azoospermia caused by
either obstruction or by germinal failure, ICSI may be performed
successfully. Of all the factors studied, the only factor that seems
to matter is the age of wife and her ovarian reserve”.(Silber 1998)

Age of wife

Under 20 --- 40% Live Deliveries / Cycle

Under 35 --- 34%

Under 40 --- 13%

Above 40 --- 04% Live Deliveries / Cycle

ICSI is actually the assisted fertilization technique with highest
incidence of pregnancies & “take home baby rate” ( Garcea 1998)

10. If ICSI is the ultimate “Cure All” or “Panacea" then
will there be “Disuse Atrophy”
of the branch called Andrology?

For the answer let us look at the 'text book' list of ICSI
indications.

Immotile Cilia Syndrome

Testicular/ Epididymal sperm retrieval(Azoospermia
cases)

Globozoospermia

Frozen- thawed sperm with poor survival

Poor fertilization with previous IVF attempt

Severe O.A.T., Necrospermia.

11. Era of ICSI
Now let us examine the first indication for ICSI
viz.” Immolite Cilia Syndrome”.
What are the 'Andrology' inputs here?
Do We just do ICSI & forget about the man and related health
issues?
No !
Look at these brain teasers.

How do we know which sperm is alive, when all Sperms
are non motile? Answer : HOST

Is sperm from ejaculate better or TESA is better for
fertilization?

Are you sure that it is a case of Kartagener's Sydrome
while talking to the couple? Answer : Difficult without
Electron Microscopy.

Are you sure it is not an E.coli seminal infection & not
Kartagener's? Answer: You should have ruled it out first.

12. Look at these brain teasers.

Kartagener's is considerd autosomal recessive but can
it be autosomal dominant or X-linked? (Ans: May be)

Are there inherited enzyme defects in Sperm Glycolysis
Metabolism, in case of 100% Immobility ?
( Glyceraldehyde-3-phospate Dehydrogenase GAPDS)
( Ans: May be)

Have you ruled out chronic sinusitis, situs inversus &
autosomal dominant Polycystic Kidney Disease?
( Ans: No, sorry I forgot.)

If you have not given regard to any of above what is
doing “just ICSI” ?. It amounts to negligence!

A Friend of mine said “Anand about 25% of my patients
of hysterectomy for menorrhagia have constipation,
weight gain lethergy”. He had not done TSH in any of
the menorrhagia cases!

13.  Regarding these issues the comment by Hector Chemes &
Craig Niederberger (J of Androl 2005 vol 26 ) is an eye
opener-
‘Should infertologists go ahead with assisted reproduction
(particularly ICSI) without a proper diagnosis of patient's
pathology? Is the role of the andrologist just to provide a
technological solution' for the couple? To physicians treating
infertility, ICSI provides a tool by which dsyfunctional, even
dead sperms may be used to fertilize the ovum. Providers of
this powerful technology may ask the question, why does one
need a complete diagnosis if the therapy is highly effective
regardless of of the aetiology, especially if the diagnosis
involves sophisticated tools & test? The answer is :- ..... these
forms of treatment involve reproduction & involve germ line
transmission to the offspring. What use is counsellings if one
does not know which disease you are dealing with?!
( Craig Niederberger 2005)

14. Welcome to S I G A
SIGA -Andromeda

15. ICSI

Too few Sperms? Use ICSI.

Too few motile Sperms? Use ICSI …

Only non motile Sperms? Use ICSI ….

Only dead Sperms ? Use ICSI …..

No Sperms ? Try Spermatids …..

No spermatids ? Try Stem cells or invitro
maturation.
Remember we are using ICSI to bypass
Sperm dysfunction. What about the causes of
dysfunction? Obviously we are neglecting
other issues pertaining to the man.

16. Issues which should not be neglected

Issues of General Health of
the man –

A- Sepsis, M .A.G.I incidence-
15 to 40 % of infertile male.

Has implications as chronic
reservoir of infection/ U.T.I.

Transmission to wife

Obstructive Azoospermia,
Necrospermia.

Affects Sperm quality ,
aptoptosis & DNA damage.

Remember ‘Swim Up’ method
does not select non- apoptotic
sperms!

17. 
Issues which Andropause
B) Hypogonadism &should not be neglected

Hypogonatrophic Hypogonadism ( 1-2% of Male in fertility)

Low FSH / LH

Low Testosterone (less than 300 ng / dL)

Severe Oligo /Azoospermia

Whitten et al (Fertil Steril 2006)
reported response to Clomiphene in a select
group.
Adult onset idiopathic form may benefit.
C.C increases LH levels and intra-testicular
testosterone.
Hussein (J Androl 2005) reported 63% rate of
sperms in
ejaculate in Nonobstructive Azoospermia cases,

18. Hypoandrogenism in infertile men

Hypoandrogenism – S. Testo < 300 ng / dL

Non obstructive Azoo 45 %

Oligospermia 43%

Normal Semen Analysis 35 %

Obstructive Azoo 17%

General Population 17%
( University of Illinois , Chicago- Aleksander
Chudnovsky and Craig Niederberger)

19. Oral Testosterone in oil :
Pharmacokinetic
Effects of 5 Alpha Reduction by
Finasteride

JOHN K. AMORY
(J of Androl. Vol. 22, 2006)
The issue of prostate stimulation was addressed.

20. Natural Selection Versus Selection
by man

Nature selects one sperm for
fertilizing depending on
normality of the sperm.
OR

Man selects one sperm for
ICISI.

Human sperm bound to the
zona pellucida have normal
nuclear chromatin as
assessed by acridine orange
fluorescence – D.Y. Liu
( Human Reproduction
Vol.22, 2007) - Sperm
binding to human ZP is highly
selective for double stranded
DNA.

21. Issues which should not be neglected
A) Genetics & Male Factor
•
Why does Varicocoele surgery fail
in some and succeed in some?
•
Which Oligo –asthenospermias will
respond to Antioxidants?
•
Why do we have fertilization failure,
Arrested Embryos & 30 to 35%
only pregnancy rate even with
good ICSI?
•
The answer could be in the ‘head’
i.e. nucleus of the Sperm !

22. Normal Spermatogenesis
depends on mitosis and meiosis in
orderly fashion …..

23. Histopathology – Biopsy – FNAC – TESE
– TESA are all interlinked with genetics
and environment …..
Open biopsy
Needle biopsy

24. Histopathology – Biopsy – FNAC – TESE –
TESA are all interlinked with genetics and
environment
Sertoli cells with sperms
Sertoli cell only syndrome

25. Histopath reporting should be as
follows

Testicular Biopsy ( Spermatogenesis Reporting)
•
Normal Testicular Biopsy : Full Spermatogenesis
in entire Biopsy and normal inter tubular tissues.
•
Hypospermatogenesis : All stages of
spermatogenesis are present , but reduced to
varying degrees.
•
Germ cell arrest : Total arrest at particular stage
most often spermatogonial or primary spermatocyte
stage. Arrest in Spermiogenesis is uncommon .
If spermatids are seen don’t call it arrest but call it
hypospermatogenesis.

26. Histopath reporting should be as
follows
4. Sertoli cell only – No tubules contain any
germ cells.
5. Seminiferous tubule Hyalinization – No germ cells.
No Sertoli cell. Fibrosis present.
6. Carcinoma in Situ – Pre invasive malignant cells
seen in place of Spermatogonia. Some tubules show
ongoing Spermatogenesis.
7. Immature testis ( Prepubertal)- Rare , seen in
hypogoado trophic Hypogonadism. Tubules lack
lumen, cells are immature Sertoli cells- Gonocytes.
Few Leydig cells.

27. Y chromosome :- Long Arm Microdeletions

28. Multiplex PCR is
used to diagnose
micro delections on
the long arm of Y
chromosomes.
These deletions are
an important cause
of male infertility. It
should be
performed in all
Azoospermic and
Oligoseprmic men.

29. Does ICSI cause any chromosomal
defects ?
• ICSI as a procedure does
Embryos ICSI-
Ejaculate
ICSI-
TESE
not cause any chromosal
defects. But ICSI using
defective Sperms form
Normal 43% 25% infertile male may transmit
Sex Chromosome
abnormalities, Autosomal
Aneuploid 26% 16% abnormalities including
translocations (13,
14),inversions and
Mosaics 26% 56% numerical abnormalities.
This is solved naturally by
nature in form of failure of
implantation……
Polyploidy 04% 06%

30. Varicocoele and Genetics

Monozygous and Dizygous twins show
different pattern of scrotal temperature.

Infertile men with varicocoele show high % of
sperms with Intense Nuclear Damage – Maria
Enciso – J of Androl. Vol. 27, 2006.

Studies on Varicocoele III : Ultrastuctural
Sperm Evaluation and 18, X & Y Aneuploidies,
Baccio M Baccetti, J of Androl. Vol. 27, 2006.

31. DNA Damage in Sperms from Men with
Varicocele
(SCD Test- Sperm chromatin dispersion)

32. Sequential FISH on SCD Processed
Spermatozoa
X= Green , Y = Red, 18 = Blue,
Halo is Blue Grey (SCD)

33. Issues which should not be neglected
Candidates for ICSI also happen to be
candidates for testicular Tumours….

High prevalence of testicular cancer in
azoopermic men
without spermatogenesis- M Mancini. Human
Reproduction Vol. 22, 2007.
The prevalence of testicular nodules and cancer
in
azoospermic men with complete SCOS is very
high. In
these subjects, the role of clinical evaluation,
ultrasound

34. Towards a non invasive method for early
detection of testicular neoplasia in semen
analysis by identification of fetal germ cell –
specific markers
C.E. Hoei – Hansen
Human Reprod vol 22, 2007
Immunocytological semen analysis based on
expression of fetal gem cell markers in exfoliated
cells has auxiliary diagnostic value , as it detects
some patients with CIS / incipient tumour but a
negative result does not exclude Testicular germ
cell tumours.

35. Immunocytological semen analysis for CIS
Positive Negative
Positive Semen
Positive
CIS Tubule

36. Sonographic Testicular Micro Lithiasis as an
indicator of pre-malignant conditions in
normal & infertile men
Sigrid V Eckardstein
( J of Androl Vol 22, 2001)

Testicular Microlithiasis (USG) can indicate
germ cell tumours.

Infertility , Testicular Mal-descent, presence of
atrophic testis are risk factors.

2.3% showed Microlithiasis & were advised
Biopsy &/or USG follow up.

Microlithiasis in presence of atrophic testes is
highly significant.

37. Breakthroughs in Andrology ?
1. Reduced Seminal Parameters associated with
environmental DDT Exposure and p,p’- DDE
Concentrations in Men in Chiapas, Mexico – A Cross
Sectional study.
Christiaan De Jager, J of Androl. Vol-27, 2006.
2. Report from Andhra Pradesh - quarry town (Kadappa)
has 5% Azoospermia rate in young married men !
(Stone Quarry Pollutants + Cotton Pesticides ) –
Embryo Talk 2006.

38. New frontiers..........
Promise & Limitations of
Germ cell transplantation in the Testis
M.D. Grisworld ( J. Anrolg. Vol 22, 2001)
In vitro culture systems hold promise of culturing
germ cells- to mature spermatozoa ( Sousa,
2002)

39. Conclusion !
• If there is azoospermia or
severe oligospermia…
• If sperms cannot undergo
Capacitation, bind to zona,
undergo acrosome reaction
or fuse with the Oocyte’s
plasma membrane … ICSI
would help.
• But , why these sperm
defects arose & what can
be done to ‘Nurturing’ the
sperm, remains the
Andrology domain …..!

40. Do We Treat Male Infertility in the Era of ICSI ?
We Do Treat Male Infertility in the Era of ICSI !
Thank You ......
 Dr. Anand K. Shinde
M. D. (Gyn )
IVF Consultant
& Director of Andrology
At “ IVF Pune”, 7th floor Deenanath Mangeshkar Hospital
Pune-4.,
Tel : 40151777

41. Dr. Anand K. Shinde
M.D
• Consultant at IVF Pune,
DMH Pune - 4
• Director Andrology IVF Pune,
DMH Pune - 4