Male factor infertility, History and investigation By: Mr Oliver Wiseman Consultant Urologist and Andrologist Read more on our website http://www.bournhall-clinic.ae

1. 01/04/2014
1
1
Male factor infertility:
History and investigation
Mr Oliver Wiseman
Consultant Urologist and Andrologist
2
Myths
• A man with azoospermia cannot become a biological
father
– donor sperm (if allowed) or adoption are the only
choices
• A man who has had chemotherapy before is sterile
and cannot father a child
• Your FSH is too high: we will never find sperm
• A man with OAT does not need to see a urologist /
andrologist
– his sperm can be used for IVF and ICSI
3
• Epidemiology
• Definitions
• Anatomy and physiology
• History
• Investigations
• Case studies
• Q and A
4
• 20-25% conception per month
• 75% at 6 months
• 85% of couples conceive in 1 year
– 15% of couples fit definition
• Further 2 years – 23% will conceive
• Another 2 years – 10% will conceive
• 10% left childless after 5 years if no action
Infertility: epidemiology
5
• 30% = entirely ♂
• 20% = ♂ + ♀
• 50% = entirely ♀
Aetiology
50%
6
• Azoospermia - The patient produces semen
containing no sperm
– Obstructive (blockage to flow)
– Non-obstructive (deficient production)
• Oligoasthenoteratozoospermia (sometimes
referred toas OAT) - less than 15 million sperm
pr ml with less than 40% total motility and more
than 96% abnormally shaped.
Definitions

2. 01/04/2014
2
7
Hormonal control of testicular function
Inhibin is a 32-kD
glycoprotein hormone
secreted primarily by Sertoli
cell.
deKretser DM, Meinhardt A, Meehan T, et al:
The roles of inhibin and related peptides in gonadal function.
Mol Cell Endocrinol 2000;161:43–46.
Anterior pituitary
testosterone levels in the
testis > 100X greater than
in the peripheral
circulation 8
Male Infertility – Urological Diagnosis
• Varicocele 42.2
• Idiopathic 22.7
• Obstruction 14.3
• NAD + female factor 7.9
• Cryptorchidism 3.4
• Immunological 2.6
• Ejaculatory dysf 1.3
• Testicular failure 1.3
• Drugs/irradiation 1.1
• Endocrine 1.1
• Infection 0.9
• Sexual dysfunction 0.3
• Systemic disease 0.3
• Sertoli cell only 0.2
• Ultrastructural defect 0.2
• Genetic 0.1
• Testis Cancer 0.1
Sigman, Lipshultz, Howards 1997
1430 male partners
9Ralph BJUI 2012 10
Male factor Evaluation
• History
• Physical Examination
• Laboratory evaluation
• Ultrasound
11
Male factor: History
• Sexual History
– Does your partner have regular cycles?
– Does she know when she ovulates?
– Do you have normal erections?
– Do you ejaculate?
• Pregnancy History
– Have you been responsible for or has your partner had any
previous pregnancies?
• Past medical and surgical history
• Drug therapy
• Gonadotoxins
12
Past Medical and Surgical
History

3. 01/04/2014
3
13
Drug History
14
• Impaired spermatogenesis
• Sulphasalazine, nitrofurantoin, methotrexate, colchicine,
chemotherapy
• Pituitary Suppression
• Testosterone, GnRH analogues
• Anti-androgenic effects
• cimetidine, spironolactone
• Drugs of abuse
• Anabolic steroids, cocaine, cannabis, heroin
• Ejaculation failure
• alpha blockers, antidepressants, phenothiazines
• Erectile dysfunction
• beta blockers, thiazide diuretics, metoclopramide
Gonadotoxic drugs
15
Gonadotoxins
• Tobacco
• Alcohol
• Cannabis
• Recreational drugs
• Anabolic Steroids
• Chemotherapy
– type and dose dependent
• Radiotherapy
• Work based chemicals (eg: solvents)
16
Recovery Potential after
chemo
Good Moderate Poor
Adriamycin Vincristine Cyclophosph
Methotrexate PEB Chlorambucil
Prednisolone ABVD Procarbazine
Cisplatin MOPP
Doxorubicin
Androgens
Oestrogens
17
……..think ahead: Preserve
Fertility
• Important that all
patients bank sperm
prior to chemo or
radiotherapy
• Patients should not
try to conceive for 2
years following
chemotherapy.
18
Physical Examination
• General
• Genitalia
– Meatus normal?
– Size of testes, consistency, location
– Any scars?
– Can you feel vas deferens?
– Is epidiymis full?
– Does the patient have a varicocoele?
• DRE

4. 01/04/2014
4
19
Lab evaluation
• Semen analysis
– Centrifugation of sperm
– Repeat analysis (need minimum of two
analyses)
– Ensure whole ejaculate collected
• Bloods
– FSH, testosterone
– Appropriate genetic tests
20
Semen analysis
• Ideally after between 2 and 5 days
abstinence
• Ensure whole ejaculate collected
• Need to do two samples, minimum
three months apart
New parameters
22
Azoospermia
23
Male reproductive anatomy: duct
system
24
Components of seminal fluid
70%
20%
10%
• Prostate
– acidic
• Seminal Vesicles
– fructose

5. 01/04/2014
5
25
Two possible patterns from SA
Low volume acidic
ejaculate
Normal volume
alkali ejaculate
Semen analysis
26
Two possible patterns from SA
Low volume acidic
ejaculate
Normal volume
alkali ejaculate
Semen analysis
27
Low volume, acidic
azoospermia
• Volume < 1cc
• Ph < 7.2
• Azoospermia
• Indicates no SV
contribution
– Fructose assay not
required
28
Low volume, acidic
azoospermia
EDO
CBAVD
• Normal sized testes
• Normal FSH
• Normal testicular
consistency
• Diagnosis:
• Vasal palpation
• TRUS
These patients have normal spermatogenesis
CFTR-­‐related
disorders
• CFTR-­‐related
disorders
include:
– Classic
cys2c
fibrosis
(CF)
– Non-­‐classic
CF
– CBAVD
• Autosomal
recessive
inheritance
• Incidence
1
in
3000,
carriers
1
in
25
• CFTR
on
Chr
7q31.2
• 100s
of
muta2ons
causing
CF
• ΔF508
=
60-­‐75%
,
next
12
=
10-­‐15%
• CFTR
29
muta2on
panel
-­‐
standard
test,
85%
of
N.
European
muta2ons
• >95%
of
males
with
CF
are
infer2le
• Azoospermia
caused
by
absent,
atrophic,
or
fibro2c
Wolffian
duct
deriva2ves
• Body
and
tail
of
epididymis
and
seminal
vesicles
abnormally
dilated
or
absent
CFTR-­‐related
disorders
• Diagnosis of CF:
– ≥1 characteristic phenotypic feature:
» Chronic sinopulmonary disease
» GI abnormalities
» Obstructive azoospermia
» Salt-loss syndrome
+ evidence of abnormal CFTR function based on one of
following:
» 2 CFTR pathogenic mutations
» 2 abnormal sweat tests
» Nasal potential difference measurements characteristic of CF
• Diagnosis of CFTR-related CAVD:
– Azoospermia
– Low volume ejaculated semen
– Absence of vas deferens (clinic or US exam, unilateral or bilateral)
– At least 1 pathogenic CFTR mutation

6. 01/04/2014
6
31
Obstructive Azoospermia:
CBAVD
• No palpable vas
• Epididymal remnant firm
• Do not need scrotal
exploration to confirm
diagnosis
• Do not need testis biopsy to
confirm diagnosis or show
spermatogenesis
• Need CF mutation analysis
(partner too)
• Need SSR (PESA)
• 20% of pts will have renal
agenesis (not related to
CFTR)
Tubular
ectasia
Abrupt tapering between
head and body of
epididymis
• Why screen for gene?
– Pt’s family
– Pt’s medical history
– Counsel couple as to chance
of offspring having CF
CFTR-­‐related
disorders
:Gene2c
tes2ng
Clinical
uses
• Confirm
diagnosis
(CF,
CBAVD)
• Ensure
partner
tested
and
counseling
arranged
• Cascade
carrier
tes2ng
in
at
risk
rela2ves
– Importance
of
a
3
genera2on
pedigree
– REFER
TO
CLINICAL
GENETICS
33
Two possible patterns from SA
Low volume acidic
ejaculate
Normal volume
alkali ejaculate
Semen analysis
34
Normal Volume Azoospermia
• SVs are present
• Ejaculatory ducts are open
• Differential diagnosis
– NOA (spematogenic failure)
– Blockage of vas or epididymis
35
Normal Volume Azoospermia
• Examination of external genitalia
• Bloods
– FSH
– Testosterone
• Differential diagnosis
– NOA (spematogenic failure)
– Blockage of vas or epididymis
36
Normal Volume Azoospermia:
Examination
Testes
Size and
consistency
Small in NOA
Normal in OA
Epididymes
Normal or full
and firm
Normal in NOA
Full and firm in
OA
Diagnosis
History

7. 01/04/2014
7
37
FSH: what is normal?
5 FSH Normal Range
This is where patients with
normal sperm production lie
Most patients with inadequate
sperm production lie here
FSH:
-High in NOA
-Normal in OA
38
Redefining normal FSH
• 610 male infertility patients from a single clinic
• AS FSH increases, semen quality decreases
• Cut off should be 4.5 iu/l….
Gordetesky et al. BJUI. 2012
39
Testosterone
Anterior pituitary
testosterone levels in
the testis > 100X
greater than in the
peripheral circulation
• High intra-testicular
levels key for
spermatogenesis
• Endogenous only
• Often lower end of ref
range
• Consider attempt to
boost
– Role of clomid
• Key to document prior
to any treatment
40
Normal Volume Azoospermia
Testes
Size and
consistency
Epididymes
Normal or full
and firm
FSH
Normal or “high”
Diagnosis
History
NOA
OA
41
To make a diagnosis in normal
volume azoospermia…
• You do not need a testis biopsy
• You do not need a vasogram
42
FSH and testicular size predict OA
and NOA
89%
96%
Schoor R et al. J Urol 2002 Jan;167(1):197-200
Testicular
biopsy not
required

8. 01/04/2014
8
43
Maturation arrest
• Possible to have
normal FSH with no
azoopermia
• Maturation arrest
beyond the
spermatocyte stage
44
Making a diagnosis in normal
volume azoospermia
• Directs treatment and further
investigations
– In NOA
• Karyotype
• Y chromosome microdeletion
• Then SSR (mTESE / TESE)
– In OA
• Reconstruction and / or sperm aspiration
45
Genetic tests in suspected
NOA
Klinefelter syndrome (47,XXY)
47
Klinefelter s syndrome
• Myths
– Your testosterone is too high to be a pt with KS
– You are too well virilised to have KS
– You are a gynecologist / urologist. You cannot have
KS
• May present with infertility
• Not necessarily hypogonadal
• Not necessarily eunichoid
• SSR can be successful
48
Klinefelter s syndrome
• Genotype
– 47, XXY (pure)
– 46, XY / 47, XXY (mosaic)
• Incidence
– 1/500 live male births
– 5-10% of azoospermics
• Spermatogenic axis failure
– Severe oligospermia, azoospermia
• Androgenic axis failure
– Failure of virilisation at puberty
– Lower testosterone in adulthood

9. 01/04/2014
9
49
• Cornell experience
– 68% retrieval
– 42% or retrievals clinical preg
– All children born were 46 XX or 46 XY
– Sperm retrieval no different from other
NOA
Klinefelter’s syndrome
Ramasamy et al. J Urol 2009 50
Region Frequency % No sperm on
TESE
AZFa 5% 100%
AZFb 35% 100%
AZFc 60% 30-50%
Yp
Yq
1
2
3
4
5
6
SRY
7
AZF a
AZF b
AZF c
Infertile
• 0.7 % oligospermic ( < 5 mil / cc)
• 10% in severe oligospermic (< 1
mil / cc)
• 15 % in azoospermia
Y chromosome microdeletion
51
Y chromosome microdeletion
• Fluctuation in sperm density is seen
over time
• There is no evidence to suggest that
sperm production decreases over time
• No other known health consequences
– Men somatically healthy
– Adequate virilisation
– Normal penile anatomy
52
Summary of genetic basis of
NOA
• Y chromosome microdeletions
– 13%
• Klinefelter s syndrome
– 5-10%
• Translocations
– 1-3%
53
Summary of how to make a
diagnosis
• Semen volume and pH are the key
– Low volume, acidic pH
• CBAVD, EDO
– Normal volume alkaline
• NOA, blockage of vas or epididymis
54
Summary of treatment options
in low volume acidic ejaculate
• EDO
– Resection of ejac duct transurethrally
– SSR: aspiration of SV, PESA or TESE
• CBAVD
– PESA or TESE

10. 01/04/2014
10
55 56
57
Summary of treatment options
in normal volume azoospermia
– In NOA
• SSR (mTESE / TESE)
– In OA
• Reconstruction and / or sperm aspiration
PESA
TESE MicroTeSE

11. 01/04/2014
11
61
Varicocoele
• Dilated & tortuous veins of
pampiniform plexus
• 15% men, 40% infertile men
– grade I palpable only with
Valsalva
– grade II are palpable with the
patient in the standing position
– grade III are visible through the
scrotal skin and are palpable
when the patient is supine
– USS only detected no effect on
fertility
• Causes OAT (dec no., motility,
morphology)
• Left most common
62
Guidelines
• ASRM / AUA
– Infertile couples with no proven female factor, if
male has abnormal semen parameters repair of
varicocoele should be considered if clinically
palpable.
• EAU
– Issue is controversial
• NICE
– men should not be offered surgery for
varicocoele as a form of fertility treatment because
it does not improve pregnancy rates
63
Pregnancy outcome in
oligospermic men
• Four RCTs, repair of clinical varicocoele in
oligospermic men
• 380 couples
• Suggestion of beneficial effect of repair, but
significant non-homogeneity of studies
– Low recruitment, high drop out rate, loss to follow
up, very high treatment arm preg rate vs very low
observation arm preg rate (considering short
duration of infertility)
• As treated analysis found difference in
favour of repair.
64
Pregnancy Outcome: ITT
65
Pregnancy Outcome: As-treated
66
Sperm Concentration

12. 01/04/2014
12
67
Sperm Motility
68
Conclusions
• Varicocoele repair associated with
– Signif improvement in sperm concentration and
sperm motility
– Reduces seminal oxidative stress and sperm DNA
damage
• There is insufficient evidence to demonstrate
a beneficial effect of repair on spont
pregnancy rates
• All methods of repair are viable options,
microsurgical repair is associated with better
outcomes and lower complication rates
69
Hormonal treatment for male factor
infertility
• Hypogonadotrophic hypogonadism
– Management by endocrinologist
– HCG +/- FSH / HMG
• For NOA
– Clomiphene citrate
– Non steroidal oestrogen receptor modulator
– Block oestrogen receptor preventing
oestrogenic inhibition of gonadotrophin
secretion
70
Action of Clomiphene
• Increases endogenous
gonadotropin-releasing hormone
secretion from the hypothalamus
and gonadotropin hormone
secretion directly from the pituitary
• Increases intra-testicular
testosterone concentration
71
Clomid
• Previous study showed use of clomiphene citrate therapy
in NOA may result in sufficient sperm for ICSI, either
– Through sperm being found to be present in the
ejaculate or
– potentially through increasing the probability of
successful microsurgical (micro)-TESE. In that study,
all patients with Sertoli-cell-only syndrome were
excluded.
• 42 pts NOA: sperm returned in 64%. Sperm found in all
remaining pts at SSR
Hussein A , Ozgok Y , Ross L , Niederberger C . Clomiphene administration for cases of nonobstructive
azoospermia: a multicenter study . J Androl 2005 ; 26 : 787 – 91
72
Niederberger Group, BJUI 2013.

13. 01/04/2014
13
73
Study protocol
• In all, 116 patients randomly chose to undergo micro-TESE
without any medical treatment and formed the control group.
• The remaining 496 patients were administered oral clomiphene
citrate at a starting dose of 50 mg every other day.
• After a minimum of 2 weeks, plasma testosterone was assayed.
The dose of clomiphene citrate was increased in increments of
25 mg every other day until morning serum testosterone was
600 – 800 ng/dL, or until 3 months had passed.
• In cases where the serum testosterone was noted to be > 800
ng/dL, the dose of clomiphene citrate was decreased to 50 mg
once every 3 days.
Niederberger Group, BJUI 2013.
74
Niederberger Group, BJUI 2013.
75
Summary
• Male fertility problems require careful
history, examination and appropriate
tests to make a diagnosis
• Working diagnosis drives further
genetic tests as well as method of and
prognosis for sperm retrieval
• Consider adjuvant treatments to help
maximise chances of sperm retrieval
76
Contact
• Copy of presentation
– http://bournhall-clinic.ae
– info@bournhall-clinic.ae