Role of Multivitamins & Antioxidants in Managing Male Infertility

Role of Multivitamins &
Antioxidants in Managing Male
Infertility
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

“Culture does not make people.
People make culture”

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.

Antioxidants
Astaxanthin several-fold stronger antioxidant activity than vitamin E and b-carotene.
potent antiperoxidation activity.
Coenzyme Q10 Protects the cell membrane from lipid peroxidation.
improves Total Antioxidant Capacity (TAC) concentrations and decreased
Malondialdehyde (MDA) levels.
L-Carnitine increases fatty acid transport into sperm mitochondria which are needed for sperm
energy production.
Lycopene antiproliferative, immunomodulatory, and anti-inflammatory effects that promote cell
differentiation .
Vitamin B9 (Folic
Acid)
Protects against mutations and DNA strand breaks.
Regulates DNA methylation and gene expression
prevents abnormal chromosomal replication and mitochondrial DNA deletions.
Zinc role in signaling, enzymatic activities, sexual maturation and managing mitochondrial
oxidative stress.
improves chromatin integrity
Selenium Suppresses testicular toxicity and modulate DNA repair.

Combined conventional/antioxidant "Astaxanthin"
treatment for male infertility: a double blind,
randomized trial
• Astaxanthin 16 mg/day or placebo for 3 months were given
Results:
• ROS and Inhibin B decreased significantly.
• Sperm linear velocity increased in the Astaxanthin group.
• The results of the zona-free hamster oocyte test* tended to improve in the
Astaxanthin group.
• A total pregnancy rate of 54.5 % in the Astaxanthin group.
• The conception per month was 23.1 % in the Astaxanthin group.
• .
Asian J Androl 2005; 7 (3): 257–262
Conclusion:
The present study suggests a positive effect of Astaxanthin on sperm parameters and fertility.

Coenzyme Q10 supplementation in infertile men with low-
grade varicocele: an open, uncontrolled pilot study
• To evaluate the antioxidant capacity of seminal plasma of infertile
men with varicocele.
• 38 patients were recruited.
• Patients underwent an oral supplementation with CoQ10 at a dosage
of 50 mg twice a day for 12 weeks.
• A semen analysis was performed at baseline and 3 months.
• Coenzyme Q10 therapy improved semen parameters and
antioxidant status.
Andrologia. 2014 Sep;46(7):805-7

The effect of L-Arginine of treatment for infertile men on
semen parameters
• L-arginine was given orally at a dose 1000 mg one capsule per day morning.
 L-arginine which provides protection against oxidative stress.
 It protects spermatozoa against lipid peroxidation by increased the release of
nitric oxide gas.
 Supplement of arginine per day to infertile men markedly increased sperm count
and motility.
 Significant elevation in the concentration of Glutathione (GSH). A significant
reductions in the concentration of Malondialdehyde (MDA), Interleukin 6 (IL-6),
and C- Reactive protein (CRP).
Tikrit Journal of Pure Science Vol. 24 (5) 2019, 1-4.
 Significant reduction in Sluggish, abnormal sperm shape and non-motile sperm
count after treatment with L-Arginine.

• 60 patients were included with 30 patients in
case and 30 patients in control groups.
• Homocysteine lowering agents were given (folic
acid 5mg, vitamin B12 500 microgram, vitamin
B6 5 mg )
• Homocysteine lowering agents were given for 6
weeks.
• Re-assessed homocysteine levels after 6 weeks.
• Outcome:
 Conceptions over a period of one year were
also noted.
• Results:
 homocysteine levels was 10.4 µmol/l
Int J Reprod Contracept Obstet Gynecol. 2013 Jun;2(2):165-171
To study the role of hyperhomocysteinemia in
unexplained infertility
Conclusions:
 Homocysteine lowering agents
have a favourable impact on the
outcomes.
 Their use is suggested in cases of
infertility associated with
hyperhomocysteinemia.

Do we understand-
“Male Infertility?”

1. 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)

Semen Report 1
Collection Method Masturbation Total Motility 41%
Abstinence 4 days Progressive
Motility
26%
Collection Complete Non
progressive
Motility
15%
Volume 2 ml Immotile 59%
Viscosity Normal Motile Sperm
Count
14.76 million
Liquefaction Time 45 minutes Normal
Morphology
5%
pH 7.6 Abnormal
Morphology
95%
Sperm
Concentration
18 million/ ml Vitality 62%
Sperm count 36 million/ ejaculate Round cells Nil

Limitations of WHO Guideline
• 5 percentile and time-to-pregnancy (TTP) concept
• Not true reference values but recommends
acceptable levels.
• Day to day variation

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?

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

Semen Report 2
Collection
Method
Masturbation Total Motility 35%
Motility
17%
Collection Complete Non progressive
Motility
18%
Count
8.4 million
Liquefaction
Time
45 minutes Normal
Morphology
3%
pH 7.6 Vitality 62%
Sperm
Concentration
12 million/ ml Round cells Nil

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

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)

When to repeat semen analysis?
• Mild problems- After 3 months
• Severe problems- ASAP
(NICE, 2013; EUA, 2018; ASRM, 2020)

Semen Report 3
Motility
16%
Motility
14%
Volume 1.5 ml Immotile 70%
Count
0.54 million
Morphology
1%
pH 7.6 Vitality 34%
Sperm
Concentration
1.2 million/ ml Round cells Nil

What next?
• Straightaway donor sperm IUI
• Antioxidants for 3 months and repeat test
• Investigate in details√
• History
• Physical Examination
• Hormone Assay
• Imaging
• Genetic Tests

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)

Sperm abnormality may be the first
symptom of testicular cancer
• 31 yrs
• Came for IUI (D)
• Malignant teratoma-
treated by orchidectomy
and chemotherapy

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.

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

Darren et al. Male infertility – The other side of the equation . 2017

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

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

In couples seeking fertility with ART, varicocele repair
• may offer improvement in semen parameters
• may decrease level of ART needed

• 14 studies (980 individuals) in the systematic review.
• Contradictory findings were reported in sperm
concentration, morphology, and motility, as well as
DNA fragmentation.
• Most included studies also raised methodological
concerns.
• Therefore, definitive conclusions about the efficacy of
antioxidant supplementation in this setting cannot be
drawn
Antioxidants in Varicocele

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

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.

B/L cryoptorchidism in ADULTS!!!

Other congenital anomalies
Transverse testicular ectopia (TTE), or
crossed testicular ectopia (CTE) Subcoronal Hypospadias

Testicular size-
Prader’s Orchidometer

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)

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
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

Stories of Hypo/Hypo
• 32, yr, H/O delayed puberty
• LH 0.06, FSH 0.02, Testo 0.63
• Anosmia
• MRI- B/L olfactory bulb absent
• Genetic tests advised, Lost to
F/U.
•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
•Advised to continue hMG

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)
•Natural conception vs ART?
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)

Antioxidants in severe male
factor?

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.

• In some studies, AS was found to be beneficial in
reversing OS-related sperm dysfunction and improving
pregnancy rates.
• The most commonly used preparations, either as
monotherapy or in combination as multi-AS, were: vitamin
E (400 mg), carnitines (500–1000 mg), vitamin C (500–
1000 mg), CoQ10 (100–300 mg), NAC (600 mg), zinc (25–
400 mg), folic acid (0.5 mg), selenium (200 mg), and
lycopene (6–8 mg).
• Still debatable due to the heterogeneity in study designs
and the multifactorial genesis of infertility.

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?

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

Semen Report 4
Collection Method Masturbation
Abstinence 5 days
Collection Complete
Volume 3.0 ml
Colour Whitish
Viscosity Normal
pH 7.8
Sperm Concentration Nil (even after centrifugation)
Round cells Nil

Semen Report 4
Abstinence 5 days
Collection Complete
Volume 3.0 ml
Colour Whitish
Viscosity Normal
pH 7.8
Sperm Concentration Nil (even after cetrigugation)
Round cells Nil

What next?
• Straightaway donor sperm IUI
• Testicular FNAC

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

• 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

• LH 30.10, FSH 43.70, E2 38.48, Testo 432

• 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

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

If previous FNAC was done (Schwarzer, 2013)
Diagnosis Chance of sperm retrieval
(Micro-TESE >> TESE)
Sertoli-cell-only syndrome
(Germ cell hypoplasia)
32%
Maturation arrest 66.7%
Hypospermatogenesis 100%
Tuberous sclerosis 33.3%
Mixed atrophy 95.2%

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

Predictors of sperm retrieval?
• FSH
• Testicular Size
• LH, Testosterone
• BMI
• AMH- semen, serum
• Inhibin B- semen, serum
• Age
• Ultrasound parameters
• 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.

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

In presence of genetic defect
• Sperm Aneuploidy testing by FISH
• PGT-SR (previously- PGD)
• Prenatal invasive testing (EUA, 2018; ASRM,
2020)

Klinefelter’s with “normal” phenotype
• 37 yr
• FSH 35.42, LH 10.13, testo 93, E2 14.45
• Undiagnosed Diabetes
• Prev FNAC- Lt side- Sertoli Only
Syndrome
• TESE – Rt side- No sperms, Lt side-
Motile Sperms

Robertsonian Translocation
45, XY rob (14, 21), (q10, q10) Sperm FISH

Alternative- Prenatal testing
(46,XY22ps+)

Genetic “abnormality” ≠ Intervention
46,XYqh- 46,XY,16qh+

Y chromosome Microdeletion (AZF)

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

Medical Therapy in Idiopathic
Azoospermia
• To improve the chance
of sperm retrieval
(Alkandari and Zini, 2021; Kumar,
2021; Holtermann et al., 2022).
• Sometimes, can lead to
appearance of sperms in
the ejaculate (Alkandari and
Zini, 2021; Kumar, 2021).
• hCG
• FSH
• CC
• Tamoxifen
• Letrozole
• Antioxidants??
(Agarwal A, Majzoub A, 2017)

Semen Report 5
Abstinence 2 days
Collection Complete
Volume 0.5 ml
Colour Whitish
Viscosity Normal
pH 6.8
Sperm Concentration Nil (even after centrifugation)
Round cells Nil

Assess
• Abstinence period
• Completeness of collection
• Usual amount of ejaculate
• Exclude retrograde ejaculation
• Suspect obstructive pathology- TRUS

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

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

CBAVD is NOT uncommon
• CFTR negative • CFTR carrier
• Wife- normal
• CFTR refused
• CFTR carrier
• Wife- normal
• CFTR negative

Semen Report 6
Motility
0%
Motility
0%
Count
Nil
Morphology
2%
pH 7.6 Vitality 12%
Sperm
Concentration
18 million/ ml Round cells Nil

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 ?

ICSI with Ejaculate vs Testicular sperms

Semen Report 7
Collection
Method
Motility
33%
Motility
13%
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

Semen Report 8
Collection
Method
Motility
33%
Motility
13%
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

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
• Consider prostatic fluid culture

A story of “Pus cells”
• 36-yr
• Apparently
unexplained infertility
• Persistent Pus cells in
semen
• Culture negative
• Pain during
intercourse
• Paraphimosis
• No pus cells after
circumcision
• Conceived after OI,
delivered

“Pus Cells” and ART outcome

Antioxidants in “Pus cells in semen”

Disclaimer
• Written consent from all the patients

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

Treatment burden for MALE
infertility falls on FEMALE

Role of Multivitamins & Antioxidants in Managing Male Infertility

Role of Multivitamins & Antioxidants in Managing Male Infertility

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