Dr Sujoy Dasgupta was invited to deliver a lecture on "Male Infertility, Antioxidants and Beyond" on 3 February in Yuvacon 2024 organized by the Bengal Obstetric and Gynaecological Society (BOGS). The session was supported by UNS.

1. Male Infertility, Antioxidants and
Beyond
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

2. I n f e r t i l i t y

3. Reproductive Consequences of ROS
and Oxidative Stress
In-Vitro Fertilization (IVF) / Intracytoplasmic
Sperm Injection (ICSI) Outcomes:
• ICSI is also affected for an excessive presence of
ROS molecules in seminal plasma and sperm.
• The damaged cell development generated by
oxidative stress, causing apoptosis and embryo
fragmentation.

4. 692 clinical studies available on CoQ10 across
therapeutic area in PubMed Index

5. • All studies report a beneficial effect of CoQ10
supplementation on semen parameters
• Although RCTs are a minority.
• Unknown- optimal dosage of CoQ10 or how it
can be combined with other antioxidant
• CoQ10 is still one of the most promising
molecules to treat idiopathic male infertility

6.  Androgen mimetic action
 Increases production of testosterone
 Enhance spermatogenesis.
 NO regulator- Promotes erection.
 Potent Anti-oxidant
 10 -100 times more powerful*
 Long lasting action- 12-hour half life
Tribulus
Terrestris
Alga Ecklonia
Bicyclis
(phloro-
tannins)5,6
 Increases NO production
 Pro –erectile effect
Chitosan
Oligosaccharide7,
8
Role of novel phytotherapies in addressing male
fertility challenges
References: 1. Ștefănescu R, et al. Biomolecules. 2020 May 12;10(5):752; 2. Salgado RM et al. Effect of oral administration of Tribulus terrestris extract on semen quality and body fat index of
infertile men, Andologia; 3. Sanagoo S, et al. Complement Ther Med. 2019;42:95-103. doi:10.1016/j.ctim.2018.09.015; 4. Chowdhury MT, et al. Journal of Environmental Biology. 2014:35:713-739; 5.
Iacono F, et al. J Steroids Hormon Sci S. 2013;5(2); 6. Lee SH, Kim SK. Biological phlorotannins of Eisenia bicyclis. Marine Algae Extracts: Processes, Products, and Applications. 2015 Feb 16:453-
64; 7. Capece M, et al. Urologia Journal. 2017 Apr;84(2):79-82; 8. Russo A, et al. Health. 2016 Dec 6;8(15):1668-78.

7. Role of Myo-inositol (MI) in improving sperm health
8
Myo-
inositol
 Promotes spermatogenesis via
 Regulation of FSH, LH & Inhibin levels
 Involved in sperm maturation
 Via activation of protein kinase B*.
 MI concentration is higher in gonads and epididymis suggesting an
involvement
 Helps in osmoregulation of seminal fluid#.
 Reduces amorphous substance in OAT spermatozoa, thereby improving
sperm motility.
 Improves mitochondrial function of sperm and increases influx of Ca2+
 Enhances fertilization ability
Reference: 1. Osman R, et al. Antioxidants. 2023 Aug 26;12(9):1673; 2. Condorelli RA, et al. Eur Rev Med Pharmacol Sci. 2011 Feb 1;15(2):129-34; 3. De Luca MN, et al. Antioxidants. 2021 Aug 13;10(8):1283; 4. Condorelli RA, et al.
Urology. 2012 Jun 1;79(6):1290-5.

8. COQ MAN in facilitating healthy sperm journey from
Inception till conception
11
Helps in
healthy Sperm
production
Helps in
Fertilization
process
Improves
Sperm
Maturation
Regulates
sperm
interaction with
Seminal fluid
Improves penile
erection,
Ejaculation and
Libido
TT and MI MI MI Chitosan
oligosaccharide
and TT
MI
Alga Ecklonia bicyclis and CoQ10- Potent antioxidant
Helps in production of good quality
sperm

9. • Empirical medical treatment (EMT) consists of
two broad categories, hormonal and
antioxidants, which can be offered to men with
idiopathic infertility (moderate recommendation)
• EMT should be offered initially for at least 4–6
months (two spermatogenic cycles) before going
for assisted reproductive techniques (weak
recommendation)

11. Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for
male subfertility. Cochrane Database Syst Rev. 2019;3(3):CD007411. Published 2019 Mar 14.
• may improve live birth rates
• clinical pregnancy rates may also increase.
• Overall, there is no evidence of increased risk of
miscarriage, however antioxidants may give more
mild gastrointestinal upsets
• Subfertilte couples should be advised that overall, the
current evidence is inconclusive.

12. Do we understand-
“Male Infertility?”

13. Obstacles in understanding male
infertility
• Male fertility outcome (pregnancy/ live birth)
depends on female factors (WHO, 2021)
• “ICSI killed Andrology” (Allan Pacey, Univ
of Sheffield)

14. Reference ranges

15. 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 spermatozoa?

16. Semen Report 1
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

17. Semen Report 1
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

18. 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

19. Severe OAT- What next?
• Straightaway donor sperm IUI
• Antioxidants for 3 months and repeat test

20. 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.

21. Detailed Evaluation
History and Examination
Darren et al. Male infertility – The other side of the equation . 2017

22. 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

23. Surgery for Varicocele
(EUA, 2018)
• Grade 3 varicocele
• Ipsilateral testicular atrophy
• Pain
• Abnormal semen parameters
• No other fertility factors in the couple

24. 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

25. Congenital bilateral absence of vas
deferens (CBAVD)
• CLINICAL DIAGNOSIS
• Semen- Volume <1.5 ml, pH <7.0, fructose negative
• Cystic fibrosis mutation (CFTR) testing (EUA, 2018; AUA/
ASRM, 2020)
• Partner testing
• Indian prevalence- 1:10,000- 1:40,000 (Kapoor et al., 2006; Prasad
et al., 2010)
• TRUS
• Renal ultrasound

26. CBAVD, TRUS, CFTR mutation
• TRUS-
• B/L agenesis of seminal vesicles
• Male partner- CFTR carrier
• Female partner- CFTR carrier

27. 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

28. 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.

29. Semen Report 2
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

30. Semen Report 2
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

31. What next?
• Straightaway donor sperm IUI
• Testicular FNAC

32. FNAC- role?
• Isolated foci of
spermatogenesis
ASRM, 2020
• Consider in indeterminate
cases- NOT NECESSARY
FSH (iu/l) >7.6 <7.6
Testicular long axis (cm) <4.6 >4.6
89% chance of NOA 96% chance of OA

33. Problems with indiscriminate FNAC- 1.
• Repeat test showed SC 3-4 sperms/ hpf
• Repeat semen analysis- 58 mil/ml, TM 48%

34. Problems with indiscriminate FNAC- 2.
• Azoospermia- one occasion
• FNAC- B/L maturation
arrest
• FSH 0.22, LH 0.34, Testo
549
• Pituitary MRI- normal
• Started hMG
• After 6 months- 2 mil/ml

35. Hormone Evaluation
FSH, LH, testosterone, HbA1C
FSH, LH low Testosterone low Hypogonadotropic hypodonadism
Pituitary MRI
Testosterone normal/
high
Androgen excess
Exogenous testosterone
Congenital adrenal hyperplasia (CAH)
Testicular adrenal rest tumors (TARTs)
History, Endocrinology referral

36. Hormone Evaluation
FSH, LH, testosterone, HbA1C
FSH, LH low Testosterone low Hypogonadotropic hypodonadism
Pituitary MRI
Testosterone normal/
high
Androgen excess
Exogenous testosterone
Congenital adrenal hyperplasia (CAH)
Testicular adrenal rest tumors (TARTs)
History, Endocrinology referral
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

37. 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
• MRI- Empty Sella syndrome

38. Problems with indiscriminate FNAC- 3.
• LH 30.10, FSH 43.70, E2 38.48, Testo 432

39. Problems with indiscriminate FNAC- 4.
• B/L testes- 6 cc each
• FNAC- B/L
maturation arrest
• FSH 37.2, LH 24.4,
Testo 245.53, E2 37
• Not keen for IVF-ICSI

40. Translocation of autosomes
45, XY rob (14, 21), (q10, q10)
Azoospermia
Robertsonian Translocation
46,XY;t(2:22)(q37;q11.21)
Severe OAT
Reciprocal Translocation

41. Genetic abnormality ≠ Advanced interventions
46,XY,15ps+
46,X,Y,q+
46,X,inv(Y)(p11.q11)
46,X,inv(Y)(p11.2q11.2)

42. Management of Male Infertility

43. 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?

44. 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

45. Role Of Medical Therapy
(EUA, 2018, ASRM, 2020)
Hypogonadotropic
hypodonadism
•hCG 2000-5000 IU 3 times a week
•If hCG alone cannot restore spermatogenesis, FSH is
added 75-150 IU 3 times a week
•Serum testosterone and semen analysis every 1–2 months
•Usual time to recover 6 – 12 months (may take 24
months)
•Often conceives at lower sperm concentration
Idiopathic Male
infertility
CC
Tamoxifen
Letrozole
hCG
All empirical
Evidences?
Testosterone
supplementation
Strongly CONTRAINDICATED
Feedback inhibition on FSH, LH→ secondary
hypogonadism
Aromatase
inhibitors (Letrozole,
Anastrozole)
If T:E2 ratio <10 (T- ng/dl, E2- pg/ml)

46. FSH Testosterone Semen Diagnosis Treatment
APHRODITE
Group 1
Low Low Abnormal
including Azoos
Hypogonadotropic
hypogonadism
hCG
(+ FSH if needed)
APHRODITE
Group 2
Normal Normal (≥350
ng/dl)
Abnormal
including Azoos
Reduced Gonadotropin
action,
functional
hypogonadism
FSH only
APHRODITE
Group 3
Normal Low Abnormal
including Azoos
Reduced Gonadotropin
action,
biochemical
hypogonadism
FSH (+hCG)
APHRODITE
Group 4
High Normal/ Low Abnormal
including Azoos
Functional
hypogonadism
hCG
(+ FSH if needed)
APHRODITE
Group 5
Normal Normal (≥350
ng/dl)
Normal Unexplained couple
infertility
?FSH only
APHRODITE Criteria, RBMO, 2024
Addressing male Patients with Hypogonadism and/or infeRtility
Owing to altereD, Idiopathic TEsticular function

47. Surgical Sperm Retrieval (SSR) in
Azoospermia (OA>NOA)

48. Can we refuse surgical sperm retrieval?
• Testicular volume 8 cc each side
• Serum FSH 20.52
FSH, testicular size or other markers-
can NOT be used for prediction/ refusal
(EUA, 2018; ASRM/AUA, 2020)

49. Predictors of sperm retrieval?
• No reliable positive prognostic factors guarantee
sperm recovery for patients with NOA
• The only negative prognostic factor is the
presence of AZFa and AZFb microdeletions.

50. Y chromosome microdeletion
AZF-a, AZF-b, AZF-c, AZF-d

51. Genetic testing
• Sperm
concentration <5
million/ml
• Azoospermia
• Testicular atrophy
• Elevated FSH
• Karyotyping
• Y chromosome
Microdeletion (YCM)
• CFTR testing in
CBAVD

52. In presence of genetic defect
• PGT-SR (previously- PGD)
• Prenatal invasive testing (EUA, 2018; ASRM,
2020)

53. • 39 yr, Azoospermia
• FSH 25.4, LH 12.6, Estradiol 14, Testo 61.
Sometimes nothing can be done

54. Disclaimer
• Written consent from all the patients

55. 1. Meticulous semen analysis in a standard
laboratory
2. Physical examination and rational investigations
3. Donor sperm is NOT the only solution
4. IUI or IVF/ICSI- depends on the overall
assessment
5. Antioxidants- May be useful in mild problem
6. Antioxidants- Not reliable in severe problem
Take Home Messages

56. Treatment burden for MALE
infertility falls on FEMALE