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Investigating Infertile Male
1. How to investigate an infertile male?
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
M Sc, Sexual and Reproductive Medicine (South Wales, UK)
Clinical Director and Consultant: Reproductive Medicine, Genome Fertility
Centre, Kolkata
Managing Committee Member, BOGS, 2022-23
Executive Committee Member, ISAR Bengal, 2022-24
Clinical Examiner, MRCOG Part 3 Examination
Winner, Prof Geoffrey Chamberlain Award, RCOG World Congress, London,
2019
3. Men’s fertility potential depends on
female factors
• Assessment of tests and treatments for the male is
challenging due to inconsistent endpoints and the
observation that many of these endpoints are
dependent upon and measured from the female
partner.
• Ideally, the endpoint for fertility trials should be "live
birth or cumulative live birth (WHO, 2021)
8. Limitations of WHO Guideline
• 5 percentile and time-to-pregnancy (TTP) concept
• Not true reference values but recommends
acceptable levels.
• Day to day variation
• Functional ability of the sperms?
9. Sperm DNA
Fragmentation (SDF)
Infertile men with:
• Repeated IUI or IVF failure
• Recurrent spontaneous
miscarriages (ESHRE, 2018)
• Previous low fertilization,
cleavage or blastulation rate
• Varicocele with
normozoospermia
• Advanced male age (>40 y)
Significance of SDF
• Live birth after IUI/ IVF/
ICSI- ?
• Oocytes can repair the
damaged DNA
• Lack of standardization
• Lack of definitive treatment
Is “Routine” Semen Analysis ENOUGH?
10. Points to note in semen report
Volume 1.4 ml
Colour Whitish
Viscosity Normal
Liquefaction Time 45 minutes
pH 7.6
Sperm Concentration 16 million/ ml
Sperm count 39 million/ ejaculate
Total Motility 42%
Progressive Motility 30%
Non progressive Motility 12%
Immotile 58%
Normal Morphology 4%
Vitality 54%
Round cells Nil
1
2
3
4
5
6
13. Semen Report 2
Collection
Method
Masturbation Total Motility 35%
Abstinence 4 days Progressive
Motility
17%
Collection Complete Non progressive
Motility
18%
Volume 2 ml Immotile 65%
Viscosity Normal Motile Sperm
Count
8.4 million
Liquefaction
Time
45 minutes Normal
Morphology
3%
pH 7.6 Vitality 62%
Sperm
Concentration
12 million/ ml Round cells Nil
14. Semen Report 2
Collection
Method
Masturbation Total Motility 35%
Abstinence 4 days Progressive
Motility
17%
Collection Complete Non progressive
Motility
18%
Volume 2 ml Immotile 65%
Viscosity Normal Motile Sperm
Count
8.4 million
Liquefaction
Time
45 minutes Normal
Morphology
3%
pH 7.6 Vitality 62%
Sperm
Concentration
12 million/ ml Round cells Nil
15. Male Infertility- Mild or Severe?
• TMSC= Total Motile sperm count =
• Sperm concentration x total volume x total motility
(16 mil/ml x 1.4 ml x 42%)
• TMSC >5/ 10/ 20 million
16. Mild Male Factor
• Investigations- NOT
usually recommended
• Antioxidants
• CC
• Other adjuvant
Lifestyle changes
1. Heat exposure to scrotum
2. Obesity
3. Food habit
4. Smoking
5. Alcohol
6. Anabolic steroids
7. Chronic scrotal fungal
dermatitis
(EUA, 2018; ASRM, 2020)
17. When to repeat semen analysis?
• Mild problems- After 3 months
• Severe problems- ASAP
(NICE, 2013; EUA, 2018; ASRM, 2020)
18. Semen Report 3
Collection Method Masturbation Total Motility 30%
Abstinence 4 days Progressive
Motility
16%
Collection Complete Non progressive
Motility
14%
Volume 1.5 ml Immotile 70%
Viscosity Normal Motile Sperm
Count
0.54 million
Liquefaction Time 45 minutes Normal
Morphology
1%
pH 7.6 Vitality 34%
Sperm
Concentration
1.2 million/ ml Round cells Nil
19. Semen Report 3
Collection Method Masturbation Total Motility 30%
Abstinence 4 days Progressive
Motility
16%
Collection Complete Non progressive
Motility
14%
Volume 1.5 ml Immotile 70%
Viscosity Normal Motile Sperm
Count
0.54 million
Liquefaction Time 45 minutes Normal
Morphology
1%
pH 7.6 Vitality 34%
Sperm
Concentration
1.2 million/ ml Round cells Nil
20. What next?
• Straightaway donor sperm IUI
• Antioxidants for 3 months and repeat test
• Investigate in details√
• History
• Physical Examination
• Hormone Assay
• Imaging
• Genetic Tests
21. Severe Male Factor is NOT ONLY a fertility
problem
• Diabetes
• Cardiovascular diseases
• Lymphoma, extragonadal
germ cell tumours, peritoneal
cancers
• Repeated hospitalization
• Increased mortality
• Testicular Cancer
Choy and Eisenberg, 2020; Bungum et
al., 2018; Eisenberg et al., 2013;
Jungwirth et al., 2018; Hotaling and
Walsh, 2009
Self-Testicular
Examination
•Atrophic Testes
•H/O undescended testicles
•Testicular microcalcification
(post-mumps or others)
22. Sperm abnormality may be the first
symptom of testicular cancer
• 31 yrs
• Came for IUI (D)
• Malignant teratoma-
treated by orchidectomy
and chemotherapy
23. Severe Male Factor- if not left
untreated ???
• Overall, 16 (24.6%) of 65
patients with severe
oligozoospermia developed
azoospermia.
• Two (3.1%)patients with
moderate oligozoospermia
developed azoospermia
• None of the patients with
mild oligozoospermia
developed azoospermia.
24. Revisiting History
• Age
• Duration of subfertility
• Previous pregnancy- can have secondary male
subfertility
• Lifestyle
• Occupation- Driving, IT, chemical industry (heavy
metal, pesticides)
• Medical history- Diabetes, Mumps, Cancer
• Surgical history- Hernia, Orchidopexy, Pituitary
Surgery, Bladder neck surgery
• Drug history- Sulphasalazine, Finesteride,
cytotoxic drugs, steroids
• Sexual history- Low libido, ED
25. Darren et al. Male infertility – The other side of the equation . 2017
26. Varicocele- always CLINICAL Diagnosis (EUA,
2018)
• Subclinical: not palpable or
visible, but can be shown by
special tests (Doppler
ultrasound).
• Grade 1: palpable during
Valsava manoeuvre, but not
otherwise.
• Grade 2: palpable at rest, but
not visible.
• Grade 3: visible at rest
27. Surgery for Varicocele
(EUA, 2018)
• Grade 3 varicocele
• Ipsilateral testicular atrophy
• Pain
• Abnormal semen parameters
• No other fertility factors in the couple
28. Do you recommend varicocelectomy here?
• 35 yr- Azoospermia
• Lt undescended testis
• 19 yr age- Lt orchidopexy
• 21 yr age- left testicular cancer
(mixed germ cell Tx)→
orchidectomy, f/b 3 cycles of
chemotherapy (BPC)
• 33 yr age-Papillary Ca Thyroid→
Total thyroidectomy and neck LN
dissection f/b Radio-iodine. Now
on Eltroxin 150
• FSH 27.14, LH 6.69, Testosterone
336 ng/dl, E2 26.0 pg/ml.
• Female age 35
29. In couples seeking fertility with ART, varicocele repair
• may offer improvement in semen parameters
• may decrease level of ART needed
30. Cryptorchidism in adults (EUA, 2018)
• In adulthood, a palpable undescended
testis should NOT be removed because it
still produces testosterone.
• Correction of B/L cryptorchidism, even in
adulthood, can lead to sperm production in
previously azoospermic men
• Perform testicular biopsy at the time of
orchidopexy in adult- to detect germ cell
neoplasia in situ
31. Cryptorchidism- bilateral in adults?
• 31 yr
• Azoospermia
• USG- Rt testis in lower abdomen, Lt testis in inguinal canal
• FSH 13.40. LH 6.87. Testo 6.89. E2 <10.
34. Importance of history and examination
Rt sided orchidopexy during appendicectomy at 18 yr
Subsequently Rt testis atrophied
Lt side operated after 6 months, could not be brought to scrotum,
biopsied, seen by MRI (not seen in USG)
35. Learning from mistake
• Secondary anejaculation and ED
• B/L abdominal testes
• 3 yr age- attempted Rt orchidopexy but
failed
• 13 yr age- Left sided orchidopexy
attempted but partial success.
• 32 yr age- B/L orchidectomy after
failed orchidopexy attempt
• 35 yr
• Left cryptorchidism (abdominal testis)
• Lt orchidectomy at 12 yr
• Testicular prosthesis
• Azoospermia
36. Imaging
Scrotal ultrasound
1. Clinically abnormal findings-
mass/ atrophy
2. Tight scrotum (Cremasteric
reflex)
3. Obese patient
• NOT for Varicocele detection
• NOT the replacement for
clinical examination
(EUA, 2018; ASRM, 2020)
Transrectal ultrasound (TRUS)
1. Low volume and pH of semen
2. Ejaculatory disorders
(EUA, 2018; ASRM, 2020)
38. Hormone Evaluation
Sperm concentration <10 million/ml
Sexual dysfunction
Clinically suspected endocrinopathy
FSH, LH, testosterone, HbA1C
FSH, LH low
Testosterone low
Hypogonadotropic hypodonadism
Pituitary imaging
hCG f/b hMG
therapy
for 6-24 months
FSH high LH high
Testosterone low
Global testicular failure
LH normal
Testosterone normal
Spermatogenesis defect
LH high
Testosterone normal
Sublinical hypogonadism
PRL, TSH If clinically suspected
Estradiol T:E2 ratio <10:1 → aromatase inhibitors
39. Stories of Hypo/Hypo
• 29 yr, Azoospermia
• Delayed puberty
• Anosmia
• MRI- B/L olfactory bulb absent
• Genetic tests advised, Lost to F/U.
•32 yr, Azoospermia
•sudden loss of body hair, low libido
•Nonfunctioning Pituitary macroadenoma →
Endoscopic surgery H/P Lymphocytic hypophysitis
•Started hCG f/b hMG by endocrinologist
•Sperm conc 1-2/ hpf
• 30 yr, Azoospermia
• 17 yr age, sudden testicular atrophy
• B/L testes 6 cc each
40. TMSC PR/CYCLE
10–20 million 18.29%
5–10 million 5.63%
<5million 2.7%
Guven et al, 2008;Abdelkader & Yeh, 2009
Hamilton etral., 2015
Criteria TMSC Treatment
Pre wash TMSC > 5 million IUI
Pre wash TMSC 1 - 5 million IVF
Pre wash TMSC <1 million ICSI
Male factor- IUI, IVF or ICSI?
41. TMSC <5 mil/ml and IUI
• Counsel before IUI
1. Double Ejaculate Kucuc et al., 2004; Oritz et al., 2016
2. “Trial IUI”- Post wash- IMSC Ombelet et al., 2014
3. IMSC >1 mil/ml → Further IUI
4. IMSC <1 mil/ml → ICSI
42. Semen Report 4
Collection Method Masturbation
Abstinence 5 days
Collection Complete
Volume 3.0 ml
Colour Whitish
Viscosity Normal
Liquefaction Time 45 minutes
pH 7.8
Sperm Concentration Nil (even after centrifugation)
Round cells Nil
43. Semen Report 4
Collection Method Masturbation
Abstinence 5 days
Collection Complete
Volume 3.0 ml
Colour Whitish
Viscosity Normal
Liquefaction Time 45 minutes
pH 7.8
Sperm Concentration Nil (even after cetrigugation)
Round cells Nil
50. Problems with indiscriminate FNAC
• B/L testes- 6 cc each
• FNAC- B/L maturation
arrest
• FSH 37.2, LH 24.4,
Testo 245.53, E2 37,
ratio <10
• Not keen for IVF-ICSI
51. Problems with indiscriminate FNAC
• 37 yr
• Inguinal hernia operated
Rt sided- 2 yr ago and
Lt sided15 yr ago
• B/L testes- 18 cc each
• FSH 5.96. LH 4.74.
Testo 212. Estradiol
14.22.
• FNAC- SCO
52. FNAC- role?
• Isolated foci of
spermatogenesis
ASRM, 2020
• Consider TESA in
indeterminate cases- NOT
NECESSARY
FSH >7.6 <7.6
Testicular long axis (cm) <4.6 >4.6
89% chance of NOA 96% chance of OA
63. Familial Azoospermia?
46,XY, dup(9)(q11-q12)
• Duplication of long arm of
chromosome 9- partial
trisomy
• FSH 4.65, LH 2.94, testo
294. Estradiol 40.
• FNAC B/L Late maturation
arrest
• Family History of
Azoospermia in
a) Own brother
b) 2 maternal uncles
c) 2 Cousin brothers (of
same maternal aunt)
75. CBAVD is NOT uncommon
• CFTR negative • CFTR carrier
• Wife- normal
• CFTR refused
• CFTR carrier
• Wife- normal
• CFTR negative
76. Semen Report 6
Collection Method Masturbation Total Motility 0%
Abstinence 4 days Progressive
Motility
0%
Collection Complete Non progressive
Motility
0%
Volume 2 ml Immotile 100%
Viscosity Normal Motile Sperm
Count
Nil
Liquefaction Time 45 minutes Normal
Morphology
2%
pH 7.6 Vitality 12%
Sperm
Concentration
18 million/ ml Round cells Nil
77. Semen Report 6
Collection Method Masturbation Total Motility 0%
Abstinence 4 days Progressive
Motility
0%
Collection Complete Non progressive
Motility
0%
Volume 2 ml Immotile 100%
Viscosity Normal Motile Sperm
Count
Nil
Liquefaction Time 45 minutes Normal
Morphology
2%
pH 7.6 Vitality 12%
Sperm
Concentration
18 million/ ml Round cells Nil
78. Steps
• Abstinence, frequency of discharge
• Place of collection
• Look for vitality- HOS, Supravital
staining
• Repeat after proper abstinence
• Can be associated with smoking, varicocele,
Immotile Cilia Syndrome
• Antioxidants ?
80. Case of total asthenospermia
• 34-yrs-old, Army-man, past smoker
• Repeated analysis- 100% immotile sperms
• Advised varicocelectomy outside
• No palpable varicocele
• Went for ICSI
• Ejaculated sperms- poor morphology
• TESA- ICSI done, Conceived
81. Semen Report 7
Collection
Method
Masturbation Total Motility 46%
Abstinence 4 days Progressive
Motility
33%
Collection Complete Non progressive
Motility
13%
Volume 2 ml Immotile 54%
Viscosity Normal Motile Sperm
Count
33.12 million
Liquefaction
Time
45 minutes Normal
Morphology
3%
pH 7.6 Vitality 32%
Sperm
Concentration
36 million/ ml Round cells Nil
82. Semen Report 7
Collection
Method
Masturbation Total Motility 46%
Abstinence 4 days Progressive
Motility
33%
Collection Complete Non progressive
Motility
13%
Volume 2 ml Immotile 54%
Viscosity Normal Motile Sperm
Count
33.12 million
Liquefaction
Time
45 minutes Normal
Morphology
3%
pH 7.6 Vitality 32%
Sperm
Concentration
36 million/ ml Round cells Nil
83. Isolated teratozoospermia
• Isolated abnormal morphology is not the
indication for ART
Penn HA, Windsperger A, Smith Z, et al. Fertil Steril. 2011; 95(7):2320–3.
84. Semen Report 8
Collection
Method
Masturbation Total Motility 46%
Abstinence 4 days Progressive
Motility
33%
Collection Complete Non progressive
Motility
13%
Volume 2 ml Immotile 54%
Viscosity Normal Motile Sperm
Count
33.12 million
Liquefaction
Time
45 minutes Normal
Morphology
5%
pH 7.6 Vitality 32%
Sperm
Concentration
36 million/ ml Pus cells 10-12/hpf
85. Semen Report 8
Collection
Method
Masturbation Total Motility 46%
Abstinence 4 days Progressive
Motility
33%
Collection Complete Non progressive
Motility
13%
Volume 2 ml Immotile 54%
Viscosity Normal Motile Sperm
Count
33.12 million
Liquefaction
Time
45 minutes Normal
Morphology
5%
pH 7.6 Vitality 32%
Sperm
Concentration
36 million/ ml Pus cells 10-12/hpf
86. MAGI (Male Accessory Gland Infection)
EUA, 2018; ASRM, 2020; Vignera et al., J Med Microbiology, 2014
• The clinical significance is controversial.
• Special Tests- Round cells vs Pus cells
• Method of collection
• Hand washing before collection
• Culture of semen
• Antibiotics- only when documented infections
• Routine antibiotics- can harm
• Consider prostatic fluid culture
• NAAT for Chlamydia and gonorrhoea
88. Semen analysis
Mild problem Severe problem
1. Lifestyle changes
2. Antioxidants
1. History
2. Physical Exam
3. Repeat semen ASAP
4. Hormonal evaluation
Low FSH, LH
Pituitary imaging
hCG/ FSH
supplementation
High FSH
Karyotype
YCM
ICSI
TESA for azoospermia
Donor sperms
Repeat semen after 3 months
Normal hormones
Cannot afford ICSI
No sperms in TESA
S/O obstruction
Idiopathic
Obstructive Azoo
TRUS
CFTR test for CBAVD
Pituitary failure Testicular failure
89. Semen analysis
Mild problem Severe problem
1. Lifestyle changes
2. Antioxidants
1. History
2. Physical Exam
3. Repeat semen ASAP
4. Hormonal evaluation
Low FSH, LH
Pituitary imaging
hCG/ FSH
supplementation
High FSH
Karyotype
YCM
ICSI
TESA for azoospermia
Donor sperms
Repeat semen after 3 months
Normal hormones
Cannot afford ICSI
No sperms in TESA
S/O obstruction
Idiopathic
Obstructive Azoo
TRUS
CFTR test for CBAVD
Pituitary failure Testicular failure
90. Semen analysis
Mild problem Severe problem
1. Lifestyle changes
2. Antioxidants
1. History
2. Physical Exam
3. Repeat semen ASAP
4. Hormonal evaluation
Low FSH, LH
Pituitary imaging
hCG/ FSH
supplementation
High FSH
Karyotype
YCM
ICSI
TESA for azoospermia
Donor sperms
Repeat semen after 3 months
Normal hormones
Cannot afford ICSI
No sperms in TESA
S/O obstruction
Idiopathic
Obstructive Azoo
TRUS
CFTR test for CBAVD
Pituitary failure Testicular failure
91. Semen analysis
Mild problem Severe problem
1. Lifestyle changes
2. Antioxidants
1. History
2. Physical Exam
3. Repeat semen ASAP
4. Hormonal evaluation
Low FSH, LH
Pituitary imaging
hCG/ FSH
supplementation
High FSH
Karyotype
YCM
ICSI
TESA for azoospermia
Donor sperms
Repeat semen after 3 months
Normal hormones
Cannot afford ICSI
No sperms in TESA
S/O obstruction
Idiopathic
Obstructive Azoo
TRUS
CFTR test for CBAVD
Pituitary failure Testicular failure
92. Semen analysis
Mild problem Severe problem
1. Lifestyle changes
2. Antioxidants
1. History
2. Physical Exam
3. Repeat semen ASAP
4. Hormonal evaluation
Low FSH, LH
Pituitary imaging
hCG/ FSH
supplementation
High FSH
Karyotype
YCM
ICSI
TESA for azoospermia
Donor sperms
Repeat semen after 3 months
Normal hormones
Cannot afford ICSI
No sperms in TESA
S/O obstruction
Idiopathic
Obstructive Azoo
TRUS
CFTR test for CBAVD
Pituitary failure Testicular failure
93. Non-targeted investigations ?
• Delayed puberty
• Testo 100.86. FSH 28.33. LH 13.65. E2 27.83
• Testosterone injection started at puberty - sec sex charac, voice, genital size
improved
• MRI pitutary microadenoma
• GH, TSH, Cortisol, PRL, - all normal
94. Targeted female investigations
• If no risk factors for
tubal block- 3 cycles of
IUI, then tubal patency
test
• If risk factors- tubal
patency first
•Ovaries
•Tubes- IUI or IVF/ICSI?
95. Meticulous semen analysis in a standard laboratory
History and Physical examination
Rational use of Hormones, Imaging, Genetic testing
Avoid non-evidence based drugs for long time
Antioxidants- May be useful in mild problem
Antioxidants- Not reliable in severe problem
Donor sperm is NOT the only solution
IUI or IVF/ICSI- depends on the overall assessment
Take Home Messages