done by my own

1. ADDIS ABABA UNIVERSTY
COLLEGE OF HEALTH SCIENCES
DEPARTMEN OF MEDICAL PHYSIOLOGY
POST GRADUATE PROGRAM (MSc)
REVIEW ON CIGARETTE SMOKING AND FERTILITY
BY: DANIEL MOLLA (ID- GSR (1278/12)
SEPTEMBER 07/2020
ADDIS ABABA, ETHIOPIA

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Table of Contents
Acknowledgment .............................................................................................................................ii
Abstract ............................................................................................................................................ii
1. Introduction.............................................................................................................................. 1
2. Objectives ................................................................................................................................ 4
3. Methods ................................................................................................................................... 4
4 . Review on cigarette smoking and fertility................................................................................. 5
4.1 Effects of cigarette smoke on folliculogenesis;..................................................................... 5
4.2 Cigarette smoking and preimplantation embryo development; ............................................ 5
4.3 Mechanisms and effects of cigarette smoke compounds on embryo development .............. 6
4.4 Cigarette smoking and embryo implantation........................................................................ 6
4.5 Effects of cigarette smoking on trophoblastic adhesion........................................................ 6
4.6 Effect and possible mechanism of smoking on male infertility ............................................ 6
4.7 Smoking and spermatozoa .................................................................................................... 7
4.8 Direct and indirect effect of smoking on male reproductive system..................................... 7
4.8.1. Epididymis..................................................................................................................... 7
4.8.2. Erectile dysfunction....................................................................................................... 7
4.8.3. Accessory glands and seminal plasma........................................................................... 8
4.8.4. Hypothalamic-pituitary-gonadal axis ............................................................................ 8
4.9 Smoking-related genetic, epigenetic and molecular alterations on male infertility.............. 9
5. Conclusion ................................................................................................................................ 10
6. References................................................................................................................................. 11

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Acknowledgment
I would like to express my special thanks of gratitude to Dr Getahun who gave me the golden
opportunity to do this wonderful article review on the topic cigarette smoking and fertility, which
also helped me in doing a lot of Research and i came to know about so many new things. I am
really thankful to you.

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Abstract
Introduction: Cigarette smoking is associated with lower fecundity rates, adverse reproductive
outcomes and a higher risk of invitro fertilization (IVF) failures. Over the last few decades,
prevalence of smoking among women of reproductive age has increased. This review focuses on
current knowledge of the potential effects of smoke toxicants on all reproductive stages and the
consequences of smoke exposure on reproductive functions.
Objectives; The aim of this review was to briefly discuss on current knowledge of tobacco
smoke effects on the reproduction process and analyses for each reproductive stage the
deleterious effects of smoke components and to explain how smoking affects female and male
fertility.
Methods: This review was compiled using published articles on the impact of cigarette smoking
and smoke constituents on the different stages of reproductive function, including
epidemiological, clinical and experimental studies. I attempted to create hypotheses and find
explanations for the deleterious effects of cigarette smoke observed in experimental studies.
These articles were obtained from PubMed data base and Google scholars through Google search
using keywords like ‘smoking and fertility’, ‘the impact of smoking on fertility.
Summary: All stages of reproductive functions are targets of cigarette smoke toxicants. Low and
high nicotine dependency increased the risk of infertility. Considering the physical, mental,
social and economic effects of infertility in society, the negative effects of smoking on fertility
should be considered and/or included in the training package for health service providers.

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1. Introduction
Infertility, one critical component of reproductive health, has been defined as failure to achieve
clinical pregnancy after regular unprotected intercourse for 12 months or more. The prevalence
of infertility has been increasing globally, and the number of couples affected by infertility has
reached 48.5 million in 2010 (1). Male infertility plays a key role in conception difficulties of up
to 40% infertile couples. Although in some men, a specific disorder may be present in the
majority; however, no apparent reason for infertility can be found. This has drawn attention to
the impact of lifestyle and environmental factors, especially diet, obesity, smoking, alcohol
intake, recreational drug use, and exposure to environmental toxins, on reproductive health of
such men (2). Tobacco smoke constituents demonstrate acute effects on female reproductive
physiology, including damaging the oocyte and altering concentrations of endogenous hormones.
In addition, smoking may have persistent effects by depleting the ovarian reserve and increasing
susceptibility to sexually transmitted infection (3).
Smoking is a well-known risk factor of reproductive health. Given a large number of smokers
worldwide as well as the reproductive toxicity induced by cigarette smoking in animal studies,
there have been growing concerns that smoking may lead to reduced fecundity in human.
Currently, available evidence suggested a causal association between maternal smoking and
reduced fertility. However, the effect of paternal smoking on fertility has been less extensively
examined, although the well-established association between male smoking and semen quality
makes this effect biologically plausible (4).
Cigarette smoke contains about 4000 compounds belonging to a variety of chemical classes
known to be toxic, including polycyclic aromatic hydrocarbons (PAH) [e.g. benzo(a)pyrene
(BaP), acenapthelene, phenanthrene, pyrene and chrysene], nitrosamines, heavy metals [e.g.
cadmium (Cd), lead and cobalt], alkaloids (nicotine), aromatic amines and so forth. These
compounds have different properties and probably different targets on the human reproductive
system. Cigarette smoking affects the human body in myriad ways, causing the development of
chronic diseases and cancers. Cigarette smoking is associated with reproductive life impairment
such as an earlier onset of menopause, higher infertility risk, lower fecundity rate and lower IVF
success rates. The WHO reports that approximately 8% of couples worldwide and 10% to 15%

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of those in industrialized nations experience infertility, and that male factor infertility is involved
in 30% to 35% of all cases (5). In order to identify possible associations between smoking and
male infertility, numerous studies have been conducted, with some reporting contradictory
results. Many studies have reported a negative impact of smoking on semen analysis parameters
and male infertility; others have found no such effects, and in some cases, have even found
positive effects on sperm motility and the extent of nuclear DNA damage in sperm. Other
inconsistent and conflicting data regarding the influence of smoking on male infertility have
been reported. Moreover, even studies reporting an effect of smoking on semen parameters have
not clearly demonstrated any effect of smoking on male fertility (5, 6,).
Smoking has been cited as a cause of infertility in both genders, but the mechanisms by which smoking
leads to infertility are not clearly understood. Most studies on smoking and infertility were conducted in
the setting of medically assisted procreation (6). A meta-analysis conducted in the late nineties showed an
OR of 1.60 (95% CI 1.34 to 1.91) for infertility among female smokers compared with non-smokers.
Among women who are of reproductive age, 30% are smokers. Women who smoked had a
significantly higher odds ratio of infertility (OR 1.60; 95% CI 1.34-1.91), in comparison to non-
smokers. The reductions in fertility among female smokers may be due to decreases in ovarian
function and a reduced ovarian reserve .The effect of smoking on female fertility appears to be dose
dependant and even secondhand smoking has been shown to reduce the chance to give birth in an assisted
reproduction programmed. Smoking during pregnancy could also decrease fertility of the future female
about to be born. One of the first cohort studies to show the association between smoking and age at
menopause was conducted in 1977. More recently, two large cohort studies of over 50 000 and 90 000
women, respectively, have shown that smoking was associated with earlier menopause. Maternalcigarette
smoking during pregnancy interferes with placental growth and functioning, and it has been proposed that
this may occur through the disruption of normal and necessary placental epigenetic patterns (7). Hormone
function is difficult to study in non-clinic-based populations because of the cyclical nature of excretion
and day-to-day variation in premenopausal women. Under the control of the complex hypothalamic–
pituitary–ovarian (HPO) axis,the steroids estrogen and progesterone are released from and reflect ovarian
activity and in turn modulate release of gonadotropins from the pituitary via a negative feedback loop. A
few studies have suggested that smokers have higher levels of FSH than do non-smokers. Creatine
kinase (CK) is an enzyme expressed by various tissues and cell types that require high energy.
This enzyme reversibly catalyzes conversion of creatine and adenosine triphosphate (ATP) to
phosphocreatine and adenosine diphosphate (ADP) (8). Its biological role is to provide an ATP

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buffering system for tissues that require large amounts of energy. Studies show that ATP and the
phosphoryl creatine shuttle are important energy sources for sperm. Therefore, we propose that
CK has an important role in sperm movement (9, 10).
Numerous researches have been undertaken regarding the effect of cigarette smoking on male
reproductive function; however, the literature that discusses this effect on human sperm CK
activity as an ATP buffering system is limited; which nicotine, cotenine and cadmium can inhibit
human sperm CK activity in an in vitro model (11, 12, 13). Moreover, in a recent meta-analysis,
female smokers experienced menopause almost a year earlier than never smokers, and this
difference was even greater in economically developed regions. For men, the literature is more
limited. Smokers tend to have lower spermatozoid absolute count, density and motility, less
semen volume and more abnormal morphology specimens than non-smokers. Interestingly, most
studies on smoking and fertility were conducted among medically assisted procreation couples,
and few data exist on the associations between smoking and fertility in the general population
(14, 15).
.

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2. Objectives
The aim of this review was;
 To describe current knowledge of tobacco smoke effects on the reproduction process and
analyses for each reproductive stage the deleterious effects of smoke components and,
 To explain how smoking affects female and male fertility.
3. Methods
This review was compiled using published articles on the impact of cigarette smoking and smoke
constituents on the different stages of reproductive function, including epidemiological, clinical
and experimental studies. For this review, who.int.hinari, gen.lib.rus.ec, Pub Med and Google
scholar were used to collect all human epidemiological and clinical studies, as well as
experimental studies with animal or cell culture models using keywords like ‘smoking and
fertility’, ‘the impact of smoking on fertility.
.

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4. Reviewon cigarette smoking and fertility
Fig: 1 the effect of tobacco smoking on different systems of the human body
4.1 Effects of cigarette smoke on folliculogenesis;
Experimental studies confirmed that when different types of animal models were exposed to
cigarette smoke metabolites, such as Cd, nicotine or BaP, regardless of the administration route
(i.p., intra-ovarian or oral), follicle loss was reported at all stages of folliculogenesis. Primordial
follicles appeared to be especially sensitive to cigarette smoke. Moreover, follicle growth was
also shown to be inhibited, with smaller-sized follicles after nicotine or BaP exposure. Follicle
growth in an isolated rat follicle culture decreased by 35% when exposed to 1.5 ng/ml of BaP, a
concentration representative of levels found in the follicular fluid of women who smoked an
average of 15cigarettes/day (5).
4.2 Cigarette smoking and preimplantation embryo development;
Several metabolites of cigarette smoke have been identified in the embryo and its environment.
BaP was detectable in the embryo, at three and eight blastomeric stages, in the cytoplasm and
nucleus. Nicotine was also identified in the endometrial and uterine fluid, suggesting that embryo
development started in a ‘toxic’ environment.

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4.3 Mechanisms and effects of cigarette smoke compounds on embryo
development
Current knowledge of the potential effects of smoking on embryo development remains poor. the
zona pellucida thickness in women who did, and did not, smoke: a thicker zonapellucida was
observed in female smokers (20.1 µm in smokers versus 15.3 µm in non-smokers). The effect of
female smoking on IVF embryo quality; found that the smoking status had no influence on
embryo morphology score, the rate of fragmentation and arrested embryos. However, a lower
fertilization rate was observed in smokers than non-smokers (78.2 versus 85.7%). Using female
mice exposed to cigarette smoke, found that the rate of growing and not arrested embryos on
Day 2 was lower in exposed mice as compared with controls (32 versus 75%) (6, 7).
4.4 Cigarette smoking and embryo implantation
Embryo implantation requires a properly prepared endometrium. Site and quality of implantation
play a major role in determining the risk of morbidity and mortality during pregnancy.
Impairment of embryo implantation was suspected in cigarette smokers: lower implantation rates
were observed in smokers who underwent IVF, even if the results were controversial. Using
human oocyte donation models, studied implantation rates in recipients according to their
smoking status: implantation rates were lower in heavy smokers (>10 cigarettes/day) than in
non-smokers (25.8 and 32.3%, respectively) (8).
4.5 Effects of cigarette smoking on trophoblastic adhesion
Histological studies of first trimester placenta demonstrated that smoking was associated with
abnormal placental morphology such as a thinner syncytiotrophoblast, fewer villous
cytotrophoblasts, a discontinuous cytotrophoblast layer, presence of highly circonvoluted fetal
blood vessels, an increased number of blindly ending cytotrophoblast columns and fewer
anchoring villi (9).
4.6 Effect and possible mechanism of smoking on male infertility
In studies investigating the influence of cigarette smoke on semen quality, most researchers have
studied semen parameters based on the basic WHO recommendations for semen analysis, which
include volume, count, concentration, motility, and morphology. In a meta-analysis reported that
the sperm concentration in smokers was approximately 13% lower than in non-smokers on

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average. Among normal healthy males, a 24% lower sperm concentration was observed in
smokers in comparison to non-smokers (10, 11).
4.7 Smoking and spermatozoa
An important biological activity is sperm motility, Creatine kinase is an enzyme expressed by
cells, such as spermatozoa, that require large amounts of energy. It plays a major role in
adenosine triphosphate (ATP) and adenosine diphosphate metabolism, and also provides an ATP
buffering system. creatine kinase activity in sperm was reduced in smokers, affecting sperm
motility and overall fertility.
Acrosin is a proteolytic enzyme that is released by the sperm when it comes into contact with an
ovum, degrading the zona pellucida of the oocyte and allowing the sperm to penetrate it.
Smokers have been found to display lower acrosin activity than non-smokers, even in the
presence of normal semen parameters (12).
4.8 Direct and indirect effect of smoking on male reproductive system
4.8.1. Epididymis
The epididymis is the site of spermatozoa maturation where sperm develop their tails. However,
the adequate maturation of sperm is known to be inhibited by various factors, including smoking
. Detached ciliary tufts have been detected in the semen of smokers. It is thought that detached
ciliary tufts are derived from the epithelium of the epididymal lining. Detached ciliary tufts may
indicate a testicular pathology with an epididymal involvement as a consequence of smoking.
4.8.2. Erectiledysfunction
Both firsthand and secondhand smoking has been conclusively proven to be modifiable risk
factors for erectile dysfunction. In a systematic review that included four prospective cohort
studies and four case-control studies reported that smoking significantly increased the risk of
erectile dysfunction. Smoking cessation significantly improved both physiological and sexual
health in male smokers, regardless of their baseline level of erectile dysfunction.

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4.8.3. Accessoryglandsandseminal plasma
The accessory sex glands of the male reproductive tract include the prostate gland, seminal
vesicles, and bulbourethral glands. The role of these accessory glands is to secrete a fluid that
helps maintain the normal homeostasis of spermatozoa once they leave the epididymis, where
they have matured and gained motility. Seminal fluid contains enzymatic and non-enzymatic
antioxidants as well as physiological ROS.
The function of the accessory glands in smokers has been studied through the evaluation of a
number of glandular markers in the ejaculate, including N-acetyl amino sugar, total phosphate (a
marker of the functionality seminal vesicles), zinc, acid phosphatase (a marker of prostate gland
functionality), and alpha-1,4-glucosidase (a marker of epididymal function). It was found that
smoking reduced both vesicular and prostatic parameters in smokers.
4.8.4. Hypothalamic-pituitary-gonadal axis
Nicotine can alter the hypothalamic-pituitary axis by stimulating the release of growth hormone,
cortisol, vasopressin, and oxytocin, which in turn inhibit luteinizing hormone (LH) and prolactin.
In a study assessing the effects of tobacco smoking on hormone levels reported that mean
estradiol levels were higher and mean levels of LH, follicle-stimulating hormone (FSH), and
prolactin were lower in smokers than in non-smokers (12,13,14).

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4.9 Smoking-related genetic, epigenetic and molecular alterations on male
infertility
Tobacco smoke contains harmful compounds and generates reactive intermediates, such as ROS
and reactive nitrogen species, which can induce multiple genetic and epigenetic changes.
Through the interaction of these intermediates, exposure to tobacco smoke can directly or
indirectly cause the formation of DNA and protein adducts, mutations, chromosomal
abnormalities, micronucleus formation, sister chromatid exchange (SCE), and promoter
methylation. Interestingly, even tissues that are not directly exposed to tobacco smoke show
elevated levels of DNA adducts due to indirect systemic exposure (15).
Fig: 2 shows how tobacco reduce sperm concentration, motility, decrease fertilization, miscarriage etc

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5. Conclusion
First and foremost, tobacco smoking leads to reduced semen quality including semen volume,
sperm density, motility, viability, and normal morphology in smokers. Furthermore, reproductive
hormone system disorders, dysfunction of spermatogenesis, sperm maturation process, and
impaired spermatozoa function have also been observed in smokers. Despite the various harmful
effects of smoking on male fertility, most male smokers are still fertile but have a higher risk of
sub-fertility or infertility. Studies of natural conception in couples with a smoking male partner
fail to demonstrate a significant reduction in fecundity. While other studies indicated that
smoking is associated with lower fecundity rates, a higher risk of invitro fertilization failures and
adverse reproductive outcomes. The process of fertilization involves a sperm fusing with an
ovum, so we assume that male smokers who can generate normal spermatozoa may have the
ability of producing offspring.
The associations i observed in different study were smoking affects semen quality and sperm
DNA damage. Although the results have not been consistent, most studies reported male
smokers had lower semen quality in terms of the conventional semen characteristics (sperm
concentration, semen volume, total count, motility, and morphology) compared with
nonsmokers. And lowered semen quality has been found to be associated with infertility.
Besides, a number of studies have observed severe sperm DNA damage in male smokers, which
could be another cause of infertility, since DNA fragmentation might prevent oocyte fertilization
or embryo development.
In general nicotine dependency increases the risk of infertility. In light of the effects of infertility
on the physical, mental, social and the economic aspects in the community.training on the
negative effects of tobacco consumption on fertility should be included in the educational
packages designed for health care providers.

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6. References
1. Yang F, Li L, Chen JP, Liu XQ, Zhong CL, Yang Y, Ren YF, Yuan W, Liang H, Miao
MH. Couple's infertility in relation to male smoking in a Chinese rural area. Asian
journal of andrology. 2017;19(3):311.
2. Meri ZB, Irshid IB, Migdadi M, Irshid AB, Mhanna SA. Does cigarette smoking affect
seminal fluid parameters? A comparative study. Oman medical journal. 2013; 28(1):12.
3. Maccani JZ, Maccani MA. Altered placental DNA methylation patterns associated with
maternal smoking: current perspectives. Advances in genomics and genetics. 2015 7;
2015(5):205.
4. Dechanet C, Anahory T, Mathieu Daude JC, Quantin X, Reyftmann L, Hamamah S,
Hédon B, Déchaud H. Effects of cigarette smoking on reproduction. Human reproduction
update. 2011; 17(1):76-95.
5. Onor IO, Stirling DL, Williams SR, Bediako D, Borghol A, Harris MB, Darensburg TB,
Clay SD, Okpechi SC, Sarpong DF. Clinical effects of cigarette smoking: epidemiologic
impact and review of pharmacotherapy options. International journal of environmental
research and public health. 2017; 14(10):1147.
6. Cui X, Jing X, Wu X, Wang Z, Li Q. Potential effect of smoking on semen quality
through DNA damage and the downregulation of Chk1 in sperm. Molecular medicine
reports. 2016; 14(1):753-61.
7. Windham GC, Mitchell P, Anderson M, Lasley BL. Cigarette smoking and effects on
hormone function in premenopausal women. Environmental health perspectives. 2005;
113(10):1285-90.
8. Ghaffari MA, Rostami M. The effect of cigarette smoking on human sperm creatine
kinase activity: as an ATP buffering system in sperm. International journal of fertility &
sterility. 2013; 6(4):258.
9. Sharma R, Biedenharn KR, Fedor JM, Agarwal A. Lifestyle factors and reproductive
health: taking control of your fertility. Reproductive Biology and Endocrinology. 2013;
11(1):66.
10. Harlev A, Agarwal A, Gunes SO, Shetty A, du Plessis SS. Smoking and male infertility:
an evidence-based review. The world journal of men's health. 2015; 33(3):143-60.

16. 12 | P a g e
11. Dai JB, Wang ZX, Qiao ZD. The hazardous effects of tobacco smoking on male fertility.
Asian journal of andrology. 2015; 17(6):954.
12. Sarokhani M, Veisani Y, Mohamadi A, Delpisheh A, Sayehmiri K, Direkvand-
Moghadam A, Aryanpur M. Association between cigarette smoking behavior and
infertility in women: a case-control study. Biomed Res Ther. 2017; 4(10):1705-15.
13. Oboni JB, Marques-Vidal P, Bastardot F, Vollenweider P, Waeber G. Impact of smoking
on fertility and age of menopause: a population-based assessment. BMJ open. 2016;
6(11).
14. Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari J, Andersson AM,
Eisenberg ML, Jensen TK, Jørgensen N, Swan SH, Sapra KJ, Ziebe S. Male reproductive
disorders and fertility trends: influences of environment and genetic susceptibility.
Physiological reviews. 2016; 96(1):55-97.
15. Radin RG, Hatch EE, Rothman KJ, Mikkelsen EM, Sørensen HT, Riis AH, Wise LA.
Active and passive smoking and fecundability in Danish pregnancy planners. Fertility
and sterility. 2014; 102(1):183-91.

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