Ebook Biennial review of infertility (Vol 3): Part 1

Peter N. Schlegel · Bart C. Fauser
Douglas T. Carrell · Catherine Racowsky
Editors

Biennial Review
of Infertility
Volume 3
2013

123


Biennial Review of Infertility



Peter N. Schlegel • Bart C. Fauser
Douglas T. Carrell • Catherine Racowsky
Editors

Biennial Review
of Infertility
Volume 3


Editors
Peter N. Schlegel
Department of Urology
Weill Cornell Medical Center
New York Presbyterian Hospital
New York, NY, USA

Douglas T. Carrell
University of Utah School of Medicine
Salt Lake City, UT, USA

Bart C. Fauser
Department of Reproductive Medicine
University Medical Center Utrecht
Utrecht, The Netherlands
Catherine Racowsky
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinlogy
and Infertility
Brigham and Women’s Hospital
Boston, MA, USA

ISBN 978-1-4614-7186-8
ISBN 978-1-4614-7187-5 (eBook)
DOI 10.1007/978-1-4614-7187-5
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2013938378
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Volume 3 of Biennial Review of Infertility is dedicated to the
spirit of lifelong service to patients, trainees, and colleagues
exemplified by Dr. Arnold Belker.



Preface

This third edition of Biennial Reviews of Fertility continues to build on a
reputation of overviewing evolving fields that are important for the field of
Reproductive Medicine. Each chapter is written by a leader in the field, who
provides critical analysis of the developing subject for readers interested in
staying on top of each area. Although books are typically viewed as having a
longer “publication lag,” limiting how timely the subject matter can be, the
compilation of expert-reviewed cutting edge topics in this book is unique. For
this reason, our reviews are updated biennially.

Since the “jury is still out” on a number of cutting edge topics, we have
expanded our section of “Controversies.” This portion of the book aims to
provide critical insights on newer areas of investigation or treatment by having two different experts provide point–counterpoint evaluation of important
topical subjects. In this issue, we are fortunate to have a balanced discussion
of the issue of the safety of the ICSI procedure by its inventor, Dr. Gianpiero
Palermo, with balanced inputs from both Doug Carrell and Kurt Barnhart.
The role of IUI in modern reproductive medicine is debated by senior authors
Erica Johnstone and Fulco van der Veen. Dr. Juergen Liebermann addresses
the role of vitrification of human oocytes. The provocative topic of another
chapter is, “Should we eliminate fresh embryo transfer from ART,” addressed
by Catherine Racowsky, Dan Kaser, and Maria Assens.
The role of aging in reproduction is addressed for both male and females
by Kenneth Aston and Stephanie Sherman, respectively. Other topics include
the role of sperm retrieval for couples with prior failed ART attempts, thoughtfully reviewed by Robert Oates, with an overview of the most recent metaanalyses of supplements for male infertility by Peter Schlegel. Dr. Raphi
Ron-El covers the ethical issues and extent of Reproductive Tourism, a growing topic of special significance in European countries where substantial
restrictions on reproductive options have been introduced.
Not only do our chapters cover every area from female reproduction to
genetics to male reproduction to assisted reproduction, but we have also
added a section on study design to help our readers better interpret published
literature in reproductive medicine. In this volume, the role of prospective
cohort study design for trials in reproductive health is discussed by Stacey
Missmer and Germaine Buck-Louis.

vii


Preface

viii

Each topic is obviously presented by a leader in the field of reproductive
medicine. We thank our authors for the very short time line that is required
for production of a timely set of reviews and the obvious other commitments
that these authors have in our field. We appreciate the thoughtful and critical
insights provided by our authors and hope that you recognize the value of
these efforts as well.
New York, NY, USA
Utrecht, The Netherlands
Salt Lake City, UT, USA
Boston, MA, USA

Peter N. Schlegel, M.D.
Bart C. Fauser, M.D.
Douglas T. Carrell, Ph.D.
Catherine Racowsky, Ph.D.


Contents

Part I

Male Infertility

1

Supplements to Enhance Male Fertility....................................
Peter N. Schlegel

2

Poor Quality Ejaculate Sperm: Do the Data Support
the Use of Testis Sperm? .............................................................
Robert D. Oates

3

The Aging Male and Impact on Offspring................................
Timothy G. Jenkins, Kenneth I. Aston, and Douglas T. Carrell

4

Testosterone Replacement Therapy in Men: Effects
on Fertility and Health ...............................................................
Peter T.K. Chan

Part II
5

6

3

9
17

31

Female Infertility

A Practical Approach to Recent Advances

in Ovarian Reserve Testing ........................................................
Benjamin Leader and Valerie L. Baker

51

Maternal Age and Oocyte Aneuploidy:
Lessons Learned from Trisomy 21 ............................................
Stephanie L. Sherman, Emily G. Allen, and Lora J.H. Bean

69

7

Fertility Preservation for Cancer Patients ................................
Suneeta Senapati and Clarisa R. Gracia

8

Reproductive Surgery and Computer-Assisted
Laparoscopy: The New Age of Subspecialty
Surgery Is Here ...........................................................................
Shane T. Lipskind and Antonio R. Gargiulo

87

101

Part III Assisted Reproduction Techniques
9

Advances in Systems for Embryo Culture ................................
Roberta Maggiulli, Lisa Dovere, Filippo Ubaldi,
and Laura Rienzi

127

ix


Contents

x

10

11

12

Patient-Tailored Approaches to Ovarian
Stimulation in ART .....................................................................
Theodora C. van Tilborg, Frank J.M. Broekmans,
Helen L. Torrance, and Bart C. Fauser
Cryopreserved Oocyte Banking: Its Prospects
and Promise .................................................................................
Kathryn J. Go, Zsolt Peter Nagy, and Ching-Chien Chang
Reproductive Tourism ................................................................
Raphael Ron-El

137

155
163

Part IV Evolving Controversies in Contemporary
Reproductive Medicine
13

Intrauterine Insemination: An Ineffective Treatment .............
Erica B. Johnstone and Jessie Dorais

14

IUI Is a Valuable and Cost-Effective Therapy
for Most Couples .........................................................................
Lobke M. Moolenaar, Bradley J. Van Voorhis,
and Fulco van der Veen

15

16

17

18

19

173

185

Vitrification of Human Oocytes and Embryos:
An Overview ................................................................................
Juergen Liebermann

189

Should We Eliminate Fresh Embryo Transfer
from ART? ...................................................................................
Daniel J. Kaser, Maria Assens, and Catherine Racowsky

203

ICSI Is a Revolutionary Treatment of Male Infertility
That Should Be Employed Discriminately
and Further Studied ...................................................................
Douglas T. Carrell
The Need for Long-Term Follow-Up of Children
Conceived Through ICSI............................................................
Rachel Weinerman, Kurt T. Barnhart, and Suleena Kansal Kalra
Popularity of ICSI .......................................................................
Gianpiero D. Palermo, Queenie V. Neri, Trina Fields,
and Zev Rosenwaks

215

223
233

Part V Clinical Research Design
20

Cohort Designs: Critical Considerations
for Reproductive Health .............................................................
Stacey A. Missmer and Germaine M. Buck Louis

247

Index .....................................................................................................

259


Contributors

Emily G. Allen, Ph.D. Department of Human Genetics, Emory University
School of Medicine, Atlanta, GA, USA
Maria Assens, M.D. Department of Obstetrics, Gynecology and
Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA
Kenneth I. Aston, Ph.D., H.C.L.D. Andrology and IVF Laboratories,
Division of Urology, Department of Surgery, University of Utah School of
Medicine, Salt Lake City, UT, USA
Valerie L. Baker, M.D. Division of Reproductive Endocrinology and
Infertility, Department of Obstetrics and Gynecology, Stanford University
School of Medicine, Palo Alto, CA, USA
Kurt T. Barnhart, M.D., M.S.C.E. Penn Fertility Care, Department of
Obstetrics and Gynecology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA

Women’s Health Clinical Research Center, Department of Obstetrics and
Gynecology, University of Pennsylvania, Philadelphia, PA, USA
Lora J.H. Bean, Ph.D. Department of Human Genetics, Emory University
School of Medicine, Atlanta, GA, USA
Frank J.M. Broekmans, M.D. Department of Reproductive Medicine and
Gynaecology, University Medical Center Utrecht, CX Utrecht, The
Netherlands
Douglas T. Carrell, Ph.D., H.C.L.D. Andrology and IVF Laboratories,
Department of Surgery (Urology), University of Utah School of Medicine,
Salt Lake City, UT, USA
Department of Obstetrics and Gynecology, University of Utah School of
Medicine, Salt Lake City, UT, USA
Department of Human Genetics, University of Utah School of Medicine, Salt
Lake City, UT, USA
Peter T.K. Chan, M.D., C.M., M.Sc., F.R.C.S.(C), F.A.C.S. Male
Reproductive Medicine, Department of Urology, McGill University Health
Center, Montreal, QC, Canada

xi


xii

Ching-Chien Chang, Ph.D. Reproductive Science Center, University of
Massachusetts, Lexington, MA, USA
Jessie Dorais, M.D. Reproductive Endocrinology and Infertility,
Utah Center for Reproductive Medicine, University of Utah, Salt Lake City,
UT, USA
Lisa Dovere, B.S. GENERA Centre for Reproductive Medicine, Clinica
Valle Giulia, Rome, Italy

Bart C. Fauser, M.D., Ph.D. Department of Reproductive Medicine
and Gynaecology, University Medical Center Utrecht, Utrecht, The
Netherlands
Trina Fields, B.S. The Ronald O. Perelman and Claudia Cohen Center for
Reproductive Medicine, Weill Cornell Medical College, New York, NY,
USA
Antonio R. Gargiulo, M.D. Department of Obstetrics, Gynecology and
Reproductive Biology, Harvard Medical School, Boston, MA, USA
Center for Robotic Surgery, Brigham and Women’s Health Care, Center for
Infertility and Reproductive Surgery, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA
Kathryn J. Go, Ph.D. Reproductive Science Center, University of
Massachusetts, Lexington, MA, USA
Department of Obstetrics and Gynecology, University of Massachusetts
Medical School, Worcester, MA, USA
Clarisa R. Gracia, M.D., M.S.C.E. Department of Obstetrics and
Gynecology, University of Pennsylvania, Philadelphia, PA, USA
Timothy G. Jenkins, B.S. Andrology and IVF Laboratories, Department of
Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
Erica B. Johnstone, M.D., M.H.S. Reproductive Endocrinology and
Infertility, Utah Center for Reproductive Medicine, University of Utah,
Salt Lake City, UT, USA
Suleena Kansal Kalra, M.D., M.S.C.E. Penn Fertility Care, Department of
Obstetrics and Gynecology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA
Daniel J. Kaser, M.D. Department of Obstetrics, Gynecology and
Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA, USA
Benjamin Leader, M.D., Ph.D. Clinical Research Division, ReprosSource
Inc., Woburn, MA, USA

Juergen Liebermann, Ph.D., H.C.L.D. In Vitro Fertilization Laboratory,
Fertility Centers of Illinois, River North Center, Suite, Chicago, IL, USA

Contributors


Contributors

xiii

Shane T. Lipskind, M.D. Department of Obstetrics, Gynecology and
Reproductive Biology, Harvard Medical School, Boston, MA, USA
Germaine M. Buck Louis, Ph.D., M.S. Division of Epidemiology, Statistics
and Prevention Research, Eunice Kennedy Shriver National Institute of Child
Health and Human Development, Rockville, MD, USA
Roberta Maggiulli, B.S. GENERA Centre for Reproductive Medicine,
Clinica Valle Giulia, Rome, Italy
Stacey A. Missmer, Sc.D. Department of Obstetrics, Gynecology, and
Reproductive Biology, Brigham and Women’s Hospital, Harvard Schools of
Medicine and Public Health, Boston, MA, USA
Lobke M. Moolenaar, M.D. Center for Reproductive Medicine, Academic
Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Zsolt Peter Nagy, Ph.D. Reproductive Science Center, University of
Massachusetts, Lexington, GA, USA
Queenie V. Neri, M.Sc. The Ronald O. Perelman and Claudia Cohen Center
for Reproductive Medicine, Weill Cornell Medical College, New York, NY,
USA
Robert D. Oates, M.D. Department of Urology, Boston University School
of Medicine and Boston Medical Center, Boston, MA, USA
Gianpiero D. Palermo, Ph.D., M.D. The Ronald O. Perelman and Claudia

Cohen Center for Reproductive Medicine, Weill Cornell Medical College,
New York, NY, USA
Catherine Racowsky, M.D. Department of Obstetrics and Gynecology,
Division of Reproductive Endocrinlogy and Infertility, Brigham and Women’s
Hospital, Boston, MA, USA
Laura Rienzi, M.Sc. GENERA Centre for Reproductive Medicine, Clinica
Valle Giulia, Rome, Italy
Raphael Ron-El, M.D. Fertility and IVF Unit, Department of Obstetrics &
Gynecology, Assaf Harofeh Medical Center, Sackler Medical School,
Tel Aviv University, Tel Aviv, Israel
Zev Rosenwaks, M.D. The Ronald O. Perelman and Claudia Cohen Center
for Reproductive Medicine, Weill Cornell Medical College, New York, NY,
USA
Peter N. Schlegel, M.D. Department of Urology, Weill Cornell Medical
Center, New York Presbyterian Hospital, New York, NY, USA
Suneeta Senapati, M.D. Department of Obstetrics and Gynecology,
University of Pennsylvania, Philadelphia, PA, USA
Stephanie L. Sherman, Ph.D. Department of Human Genetics, Emory
University School of Medicine, Atlanta, GA, USA


xiv

Helen L. Torrance, M.S. Department of Reproductive Medicine and
Gynaecology, University Medical Center Utrecht, CX Utrecht, The
Netherlands
Filippo Ubaldi, M.D., M.Sc. GENERA Centre for Reproductive Medicine,
Clinica Valle Giulia, Rome, Italy
Theodora C. van Tilborg, M.D. Department of Reproductive Medicine and
Gynaecology, University Medical Center Utrecht, CX Utrecht, The

Netherlands
Bradley J. Van Voorhis, M.D. Center for Advanced Reproductive Care,
University of Iowa, Iowa City, IA, USA
Fulco van der Veen, M.D., Ph.D. Amsterdam Academic Medical Centre,
University of Amsterdam, Amsterdam, North-Holland, The Netherlands
Rachel Weinerman, M.D. Penn Fertility Care, Department of Obstetrics
and Gynecology, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA

Contributors


List of Abbreviations

3D
AAGL
AC
AFC
AM
AMH
ART
AS
ASD
ASDP
ASRM
BMP-15
BWS
CAG
CBRC
CC

CCCT
CCSS
CDC
CET
CI
CLIA
COH
CONSORT
COS
CP
CPA
CPAP
cPR
DES
DFI
DHEA
DHT
DM

Three-dimensional
American Association for Gynecologic Laparascopists
Artificial collapsing
Antral follicle count
Abdominal myomectomy
Anti-Mullerian hormone
Assisted reproduction technologies
Angelman Syndrome
Autism spectrum disorders
Atlanta Down Syndrome Project
American Society for Reproductive Medicine

Bone morphogenetic protein-15
Beckwith–Wiedemann Syndrome
Cystone adenine guanine
Cross-border reproductive care
Clomiphene citrate
Cytosine (×3) thymine
Childhood cancer survivorship study
Centers for Disease Control and Prevention
Cryopreserved embryo transfer
Confidence interval
Clinic Laboratory Improvement Act
Controlled ovarian hyperstimulation
CONSistentcy in r-FSH starting dOses for individualized
tReatmenT
Controlled ovarian stimulation
Cerebral palsy
Crioprotectant
Continuous positive airway pressure
Clinical pregnancy rate
Diethylstilbestrol
DNA Fragmentation Index
Dehydroepiandrosterone
Dihydrotestosterone
Myotonic dystrophy

xv


List of Abbreviations

xvi

DMSO
DNA
DNAH11
DNAH5
dUTP
E2
EFORT
EG
eNOS
ERCP
ES
eSET
ET
EUROCAT
FASTT
FDA
FET
FORT-T
FSH
GEE
GGC
GH
GnRH
GO
GUTS
hCG
HDL
hMG

HOMA
HPO
HSV
HSV
HTF
HTT
ICMART
ICSI
IHH
IMSI
IPSS
IQ
IR
IUI
IVF
LDH
LH
LM
LOH

Dimethyl sulphoxide
Decoy ribonucleric acid
Dynein heavy chain 11
Dynein heavy chain 5
Deoxynucleotidyl transferase-mediated
Estradiol
Exogenous FSH ovarian reserve test
Ethylene glycol
Endothelial nitric oxide synthase
Endoscopic retrograde cholangiopancreatography

Equilibration solution
Elective single embryo transfer
Embryo transfer
European surveillance of congenital anomalies
Fast track and standard treatment trial
United States Food and Drug Administration
Frozen embryo transfers
Forty and over infertility treatment trial
Follicle-stimulating hormone
Generalized estimating equations
Guanine guanine cytosene
Growth hormone
Gonadotropin-releasing hormone
Glass oviduct
Growing Up Today Study
Human chorionic gonadotropin
High densitylipoprotein
Human menopausal gonadotropins
Homeostatic model assessment
Hypothalamic pituitary ovarian
High security vitrification kit
Hemi-straw system
Human tubal fluid
Huntingtin gene
International Committee for Monitoring Assisted
Reproductive Technology
Intracytoplasmic sperm injection
Idiopathic hypogonadotropic bypogonadism
Intracytoplasmic morphologically selected sperm injection
International prostate symptom score

Intelligence quotient
Implantation rate
Intra uterine insemination
In-vitro fertilization
Lactate dehydrogenase
Luteinizing hormone
Laparoscopic myomectomy
Late-onset hypogonadism


List of Abbreviations

xvii

LUTS
MDI
MEN
MENT
MESA
MI
MII
MRI
MTHF
NADP
NASA-TLX
NC
NDSP
OAT
ODS
OHSS

oPR
OPS
OPTIMIST
OR
ORT
PADAM
PCOS
PDE5I
PDMS
PEMT
PESA
POI
POR
PPV
PSA
PZD
RCT
REI
RFID
rFSH
rLH
RM
ROS
RR
RTR
SA/V
SART
SCD
SCSA
SES

Lower urinary tract symptoms
Mental development index
Multiple endocrine neoplasia
Methyl nortestosterone
Microsurgical epididymal sperm aspiration
Meiosis I
Meiosis II
Magnetic resonance imaging
Methylene tetrahydrofolate
Nicotinamide adenine dinucleotide
National Aeronautics and Space Administration
Task Load Index
Non cohort
National Down Syndrome Project
Oligo-astheno-teratospermia
Ovarian dysgenesis syndrome
Ovarian hyper-stimulation syndrome
Ongoing pregnancy rate
Open pulled straw
OPTIMisation of cost effectiveness through Individualized
FSH STimulation
Odds ratio
Ovarian reserve test
Partial androgen deficiency in aging men
Polycystic ovarian syndrome
Phostphodiesterase-5 inhibitors
Polydimethylsiloxane
Phosphatidylethanolamine n-methyl transferase
Percutaneous epididymal sperm aspiration

Primary ovarian insufficiency
Poor ovarian response
Positive predictive value
Prostate specific antigen
Partial zona dissection
Randomized controlled trial
Reproductive endocrinology and infertility
Radio frequency identification
Recombinant follicle stimulating hormone
Recombinant luteinizing hormone
Robot-assisted laparoscopic myomectomy
Reactive oxygen species
Relative risk
Robotic tubal reanastomosis
Surface area-to-volume
Society of Assisted Reproductive Techniques
Sperm chromatin dispersion test
Sperm chromatin structure assay
Social economic status


List of Abbreviations

xviii

SHBG
SITA
SRS
SSS
STS

SUZI
TB
TDS
TECS
TESA
TESE
TIC
TRT
TTP
TUNEL
uFSH
USPHS
VS
WHO
WOW

Sex hormone binding globulin
Standard infertility treatment algorithm
Society of Reproductive Surgeons
Synthetic serum substitute
Small tandem repeat
Sub-zonal sperm injection
Testosterone buciclate
Testicular dysgenesis syndrome
Tilting embryo culture system
Testicular sperm aspiration
Testicular sperm extraction
Timed intercourse
Testosterone replacement therapy
Time-to-pregnancy

Terminal deoxynucleotidyl transferase dUTP nick end labeling
Purified urinary follicle stimulating hormone
US Public Health Service
Vitrification solution
World Health Organization
Well of the Well


Part I
Male Infertility


1

Supplements to Enhance Male
Fertility
Peter N. Schlegel

1.1

Introduction

Nutritional supplements are not regulated by the
Food and Drug Administration and are distributed
from a wide variety of different manufacturers.
Because sperm are known to be highly susceptible
to oxidation, it is possible that antioxidant materials
could protect sperm, limit sperm DNA damage,
or enhance sperm function, including motility [1, 2].
Unfortunately, limited studies have evaluated the

role of nutritional supplements in male fertility.
Because such limited studies have been published,
it is possible, and quite likely, that a publication
bias exists towards positive studies. A recent
Cochran meta-analysis reported the benefit of
nutritional supplements for male fertility based
on only 20 live births [3]. In addition, most studies
on male supplements involve combination agents,
making the benefit of any individual agent difficult
to determine. In this analysis, we will discuss some
of the in vitro effects of nutritional agents on
sperm, as well as clinical trials for male infertility
patients who are attempting to conceive naturally,
and emphasize clinical trials of treatment prior to
assisted reproduction. The antioxidant agents that
have been described for potential use will be
reviewed as well.

1.2

The following agents have been described as being
nutritional supplements and represent vitamins,
minerals, and other substances that may have a
role in protecting sperm, enhancing sperm function, or potentially improving fertility both naturally and/or after assisted reproduction [4]. Each
of these agents will be reviewed in terms of its
mode of action and studies involving these agents
presented.

1.2.1

Vitamin C

Vitamin C is a high potency water-soluble reactive
oxygen species scavenger. It has been shown to
neutralize superoxide, hydroxyl, and hydrogen peroxide radicals. It is naturally concentrated in semen
at levels that are tenfold higher than that seen in
serum. Systemic therapy with vitamin C decreases
sperm DNA fragmentation, as measured by the
presence of DNA adducts in sperm. It may also
influence the expression of genes involved in intracellular redox pathways [5]. Of note, vitamin C can
act as a pro-oxidant at high doses.

1.2.2
P.N. Schlegel, M.D. (*)
Department of Urology, Weill Cornell Medical Center,
New York Presbyterian Hospital, 525 East 68th Street,
Starr 900, New York, NY 10065, USA
e-mail:

Antioxidant Agents

Vitamin E

Vitamin E is known to be a lipid-soluble antioxidant that is present in cell membranes. The presence of vitamin E protects the integrity of the
phospholipid bilayer of the cell membrane as

P.N. Schlegel et al. (eds.), Biennial Review of Infertility: Volume 3,
DOI 10.1007/978-1-4614-7187-5_1, © Springer Science+Business Media New York 2013

3

P.N. Schlegel

4

well as the mitochondrial sheath. In part, it acts as
an antioxidant by interrupting the chain reaction
of lipid peroxidation. Vitamin E can increase production of scavenger antioxidant enzymes, and it
enhances the antioxidant activity of other agents.
In vitro, it is known to protect sperm during cryopreservation [6].

It is known that defects in folate synthesis, such as
defects in MTHF reductase or PEMT enzymes, are
associated with male infertility. There is limited
evidence for a role of folate deficiency in idiopathic
male infertility [9].

1.2.6
1.2.3

Zinc

Zinc is a necessary mineral for optimal functioning of antioxidant enzymes, including superoxide
dismutase. It inhibits membrane oxidative enzymes,
such as NADP oxidase. It may also have a role in
supporting the immunological system. It is well
documented that lower zinc levels are present in
the semen of infertile males and zinc deficiency
has been associated with abnormal flagellae and

microtubular defects in sperm. It is not clear, since
zinc levels are so high in semen to begin with,
whether the relative zinc deficiency seen in infertile males is enough to affect the natural function
of this mineral. Systemic therapy is associated
with reduced seminal fluid oxidative activity,
apoptotic markers, and DNA fragmentation with a
trend towards semen parameters [7].

1.2.4

Selenium

Selenium is a mineral that is required for normal
testicular development, spermatogenesis, sperm
motility, and function [8]. It reduces antioxidative
stress by an unknown mechanism. Enzymes require
selenium for normal function, including those that
are involved in antioxidative pathways, such as
phospholipid, hydroperoxide, glutathione peroxidase. Selenium administration increases glutathione
peroxidation-1 expression, which destroys hydrogen peroxide, a potent oxidative agent.

1.2.5

Carnitine

Carnitine is a water-soluble antioxidant that is also
our primary fuel for sperm motility. Carnitine is
involved in the transport of long chain fatty acids
into the mitochondrial matrix, possibly explaining
its role in supporting sperm motility. Carnitine

increases expression of antioxidant enzymes,
including heme oxygenase-l and endothelial nitric
oxide synthase (eNOS). Carnitine enhances cellular energetics in mitochondria by facilitating the
free fatty acid entry into that organelle. Carnitines
are thought to protect sperm DNA and cell membranes from reactive oxygen species induced DNA
damage and apoptosis [10].

1.2.7

Carotenoids

Carotenoids work synergistically with selenium
and vitamin E as antioxidants. The most commonly studied carotenoid is lycopene that is naturally derived from fruits and vegetables and found
in especially high concentration in tomatoes.
Carotenoids have a high reactive oxygen species
quenching rate and are found in higher plasma levels than beta-carotene. High lycopene concentrations are found in the testes and seminal plasma.
An additional carotenoid has been described
recently, astaxanthin, a carotenoid extracted from
algae. This agent has a high number of conjugated
double bonds, making it a potent antioxidant. It is
a more potent antioxidant than vitamin E or carnitine. Its role in male fertility has only recently been
explored [11].

Folate
1.2.8

Folate reduces homocysteine concentrations by its
free radical scavenging properties. It may work
synergistically with zinc to improve semen quality.

Coenzyme Q10 (Ubiquinone)

Coenzyme Q10 functions in electron transport
and is an antioxidant. It is thought to be important


1

Supplements to Enhance Male Fertility

in mitochondrial function. It is found at high levels
in metabolically active tissues. The semen level
of coenzyme Q10 correlates with sperm concentration and motility, suggesting an intrinsic role
in the production of sperm and sperm motility.
Treatment of patients with coenzyme Q10 was
associated with improved sperm concentration
(OR = 1.6–5.5) after 6–9 months of treatment. It is
also associated with improved sperm motility
(OR = 1.4–4.5). In a small trial, couples where the
male was treated with coenzyme Q10 resulted in
nine pregnancies versus no pregnancies in the
control group (OR = 2.2, p = 0.24) [12, 13].
Coenzyme Q10 is suggested to have a benefit on
sperm production.

1.3

Quality of Antioxidant Trials

Most antioxidant trials have not been performed

in a rigorous, randomized, controlled fashion.
The scientific quality of antioxidant trials to-date
has been relatively poor, as summarized by Ross
et al. [4]. In most studies, the randomization
method was not clear and allocation concealment was not clear as well. Double blinding was
done for most of the studies, and no intention to
treat analysis was done in the majority of the
studies. Follow-up was typically strong with
most studies reporting 90–100 % follow-up rate.
Interpretation of these studies was often difficult
because multiple agents were used and in some
cases no placebo was applied. For example, in
one study by Omu et al. [7], vitamin C, vitamin
E, zinc, and other combinations of agents were
used together. Similarly, Scott et al. [14] used
vitamin A, vitamin C, vitamin E, and selenium,
many of which have not been demonstrated to
have antioxidant activities. Although most studies have suggested an odds ratio for effect of
agents that was >1, the exact benefit, if any, of
antioxidant therapies is not clear, in large part
because of likely potential publication bias. In
other words, studies were most likely to have
been published if they demonstrated a benefit of
intervention.

5

1.4

Results of Trials

1.4.1

Menevit

One of the most interesting interventional studies
was a randomized controlled trial of antioxidants
prior to IVF in a series of patients where the man
had abnormal sperm DNA fragmentation. A total
of 60 couples were enrolled. The men were
treated with lycopene 6 mg, vitamin E 400 IU,
vitamin C 100 mg, zinc 25 mg, selenium 26 mcg,
folate 0.5 mg, and garlic 1,000 mg in palm oil
vehicle. The placebo arm received palm oil vehicle alone. There was a 2:1 randomization of drug
versus placebo and treatment was provided for
3 months before IVF-ICSI. Couples had to have
had a prior failed IVF attempt and abnormal
semen parameters, suggesting oxidative stress
with abnormal sperm DNA fragmentation. The
mean pre-treatment DFI was 39 % and female
age was less than 39. The primary outcome was
reported to be embryo quality.
Unfortunately, no difference was seen in
embryo quality, and the pregnancy rate was not
statistically different (per embryo transfer).
However, the “viable pregnancy rate” differed
between treatment and placebo groups, defined
as ongoing pregnancy per embryo transferred,
46 % versus 24 %. Interestingly, the raw implantation rate in the treatment and control groups
was not different (p = 0.06), and the raw biochemical pregnancy rate was not different (p = 0.08).

Although the treatment was presumed to affect
sperm DNA fragmentation, there was actually no
repeat evaluation of sperm DNA fragmentation
during treatment, raising a question as to whether
any benefits or treatment were modulated by a
direct effect on sperm [15].

1.4.2

Vitamin E and Zinc

The Cochran collaboration reported an evaluation
of antioxidants on ART outcome. Any dose or
type of antioxidant could be compared to placebo


P.N. Schlegel

6

or no treatment. The primary outcomes were analyzed in only three studies for live births. A secondary outcome, pregnancy rate, was evaluable
in 15 studies. The Cochran meta-analysis demonstrated an odds ratio (OR) of 4.85, benefiting the
use of oral antioxidants (95 % confidence interval 1.9–12.2) for a beneficial effect on live birth
rates. The pregnancy rate was improved by an
OR of 4.8 (2.6–6.6) in favor of antioxidant use.
Interestingly, each of the studies looking at live
birth had a positive result with comparisons
involving vitamin E versus placebo [16, 17] and
oral zinc versus no treatment [7]. Overall, only
18 out of 116 experimental arm patients achieved

a live birth with 2 out of 98 in the control arm.
Despite analysis of 34 trials involving 2,876
couples undergoing ART, the primary outcome
for this meta-analysis could be determined by
only three trials. A total of 20 live births occurred
in these three trials. Both zinc and vitamin E were
used. Of note, there is significant concern about
high dose of vitamin E use and its cardiovascular
risk [18]. Interestingly, in two of the trials, there
were no pregnancies in the control arm. It is quite
unusual for an ART intervention trial to have no
pregnancies in a control arm. Using pregnancy rate
as an outcome, a larger number of studies were
involved but the antioxidants used ranged from
multiple agents, to vitamin E, to l-acetylcarnitine
plus l-carnitine, l-carnitine alone, vitamin C and
vitamin E, magnesium, coenzyme Q10, and zinc.
In the meta-analysis for pregnancy rates, a total
of 53 pregnancies were analyzed.
When the pregnancy rate was evaluated as an
outcome (admittedly, a secondary outcome for
this planned Cochran analysis) the magnitude of
benefit appeared to be greater than the effect that
would be expected by improving sperm DNA
fragmentation. Antioxidants are thought to function by decreasing sperm DNA fragmentation,
and the magnitude of benefit (OR for pregnancy
with treatment) was 4.18. One meta-analysis of
the effect of DNA fragmentation on pregnancy
rates during ART reported a diagnostic OR of
1.44 [19]. Therefore, the magnitude of benefit

(400 %) appeared to greatly outweigh the magnitude of benefit that would be suggested from
DNA fragmentation alone (44 %). Of note, the

pregnancy rate in the control group was 0–11 %
in most of the trials with 3 % as a mean value
(versus 16 % in the treatment group). This very
low pregnancy rate after assisted reproduction
suggests some concern with the type of ART performed or the site for these trials.
Taken together, only 20 pregnancies were
involved in demonstrating the treatment effect
that is proposed in the Cochran meta-analysis,
from a total of three trials. The risk of publication
bias appears to substantially affect the purported
benefit of this intervention. Multiple agents were
considered together to evaluate this effect. Even
though the magnitude of benefit (OR = 4.8) for
live births suggests benefit, it is not clear how to
interpret these results.

1.5

Summary

Antioxidants appear to have some promise as
agents that could provide a benefit of improving
fertility potential for men with abnormal sperm
DNA fragmentation, and possibly men with idiopathic infertility. The most promising agents appear
to be vitamin E, carnitines, astaxanthin, vitamin C,
zinc, and possibly coenzyme Q10. Unfortunately,
based on published data, it is impossible to make

evidence-based recommendations of a specific
agent, dose, or concoction of supplements for a
couple with male factor infertility. What dose
should be used, what combination of agents, and
the actual mechanism of action is impossible to
determine from published data. All that one can say
at this point is that antioxidants might have benefit
in the treatment of male infertility, especially for
men with abnormal sperm DNA fragmentation or
idiopathic infertility. Unfortunately, the magnitude
of benefit and treatment regimen to be recommended is yet to be determined.

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