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Lluís Bassas MD, PhD
Laboratory of Andrology and Embryology, Andrology Department
Sperm quality & fertility: clinical implications of
environmental factors & lifestyle
Disclosure of Interest: Nothing to Disclose
Classification of infertility aetiologies
Congenital factors
Cryptorchidism and anorchia (8%)
Chromosomal abnormalities (Klinefelter, Yq chromosome microdeletions, translocations, inversions) (5%)
Genetic abnormalities (CBAVD, Kallmann syndrome, mutations in genes involved in Hypothalamus–
pituitary–gonadal axis, partial/Mild Androgen Insensitivity syndrome) (2%)
Acquired factors
Testicular torsion, surgical damage to vascularisation of the testes (2%)
Post-inflammatory forms (orchitis, epididymitis), post-traumatic damage (2%)
Obstruction, subobstruction of proximal and/or distal urogenital tract (1%)
Recurrent urogenital infections, prostatitis, prostatovesciculitis (3%)
Exogenous factors (medications, cytotoxic drugs, irradiation, heat etc) (7%)
Systemic diseases (liver cirrhosis, renal failure etc) (4%)
Varicocele (12%)
Erectile dysfunction, ejaculatory dysorders (2%)
Acquired hypogonadotrophic hypogonadism or endocrine factors (2%)
Idiopathic forms
-Unknown etiology (about 50%)
2
Lifestyle and occupational risk factors
• Personal health factors – Age at reproduction attempt
– Obesity/malnutrition
– Physiological stress/Exercise
– Psychological stress
– Diet
• Physical agents – Ionizing radiations
– Electromagnetic fields
– Temperature
• Occupational – Clothing
– Sedentarism/work
• Recreational substances – Alcohol
– Smoking
– Marijuana
– Cocaine
– Opiates
– Anabolic steroids
• Environmental toxicants – Hydrocarbons
– Organic solvents
– Pesticides
– Xenoestrogens
– Metals
3
Age and reproductive fitness
4
• Partial hypogonadism (both primary and secondary)
• Lower semen volume, decreasing biochemical markers
• Reduced sperm motility, reduced normal morphology
• Increase of some sperm aneuploidies (diploidy, disomy chr. 9)
• Increased DNA fragmentation
– Additive with other causes
– Higher risk of gene mutations post-fertilization (genetic dominant dideases)
– Polygenic neurological diseases
• Lower pregnancy rates (IUI)
• Higher miscarriage rate (IUI, IVF, ICSI)
• More stillbirths
• Increased trophoblast disease
Sartorius (Hum Reprod Update, 2010)
Age & cumulative parenthood rate
5 Walschaerts (Hum Reprod, 2012)
Reproductive outcomes and paternal age
6 Yang (Hum Reprod, 2007)
Relative risk of birth defects HR of spontaneous miscarriages
Prospective data from 5121 Californian
women, men aged 20 years as referent
Slama (Am J Epidemiol, 2005)
Retrospective analysis of 5 213 248 subjects in
the USA. Increased risk for heart defects,
circulatory/respiratory defects, diaphragmatic
hernia, tracheo-oesophageal fistulas, musculo-
skeletal anomalies
Impact of BMI on semen and reproductive hormones
meta-analysis
7 MacDonald (Hum Reprod Update, 2010)
No evidence for a relationship between BMI and sperm concentration or total sperm count.
Conversely, there was strong evidence of a negative relationship for testosterone, SHBG
and free testosterone with increased BMI.
Overweight and spermatogenesis meta-analysis
8 Sermondade (Hum Reprod Update, 2013)
Od
ds
rati
os (
95
% C
I) f
or
olig
o
or
azo
osp
erm
ia
UnderW Normal OverW Obese Morbid
Acquired hypogonadotropic hypogonadism often unrecognized in adult men
9
Parameter Baseline 1 Baseline 2 After 15 weeks of
HCG treatment
Volume (mL) 0,3 0,8 2,0
pH 7,5 8,0 7,8
Sperm concentration
(x106/mL) 2,4 5,1 38
Motility (a-b-c-d) (%) 0 – 0 – 41 – 59 0 – 2 – 26 – 73 49-13-0-38
Vitality (%) 45 39 66
Normal morfology (%) 0 0 5
Teratozoospermia index 1,60 1,65 1,47
Fructose (µmol/ejaculate) 15
Zinc (µmol/ejaculate) 3,3
α-glucosidase (mU/ejaculate) 16
Testosterona (nmol/L) 2,62 2,15 28,1
17β estradiol (pmol/L) -- 19
SHBG (nmol/L) 69,2 --
LH (U/L) 0,96 1,12 3,62
FSH (U/L) 0,67 0,89
Prolactina (µg/L) 13.2 --
Sperm
iogra
ms
Horm
ones
35 y/o male
130 kg, 185 cm
BMI 37,9
Periods of weight loss
18 mo primary subfertility
Low libido
Minimal ejaculatory delay
Minimal gynecomastia
Testes volume 15 mL (R,L)
Treatment
hCG 2000 ui twice/week
Natural pregnancy
12 weeks of treatment
Long-term strenuous treadmill running & reproductive hormones & semen quality
10 Safarinejad (J endocrinol, 2007)
HIE: high intensive exercise (n=143)
MIE: moderate intensive exercise (n=143)
Significant reduction of sperm motility and morphology also seen in HIE compared to MIE
Significant reduction of LH, FSH and inhibin also seen in HIE compared to MIE
Psychological stress and sperm quality
11 Fukuda (Hum Reprod, 1996)
Sperm motility (%) before and after earthquake in
eight men (Richter scale <4)
Sperm motility (%) before and after earthquake in
seven cases suffering house destruction (Richter
scale >6)
Kobe earthquake (Jan 17, 1995)
Psychological stress and sperm quality meta-analysis
12
Concentration Progressive motility Abnormal morphology
Li (Fertil Steril, 2011)
mean 95% CI P
difference
Semen volume 0.03 -0.37, 0.32 0.88
Sperm concentration -23.01 -41.06, -4.96 0.01
Progressive motility -6.49 -10.20, - 2.78 0.0006
Abnormal morphology 7.43 2.66, 12.21 0.02
Gonadotoxic products afecting spermatogenesis
13
Alcohol 1, altered testosterone metabolism Cocaine 1 Marijuana 1 Espironolactone 1, 2, 5, 8 Ca++ blocking channels 6 Nitrofurantoíne 1, inhibits testicular cells Eritromicine 1, 7 Tetraciclins 7, afinity for spermatozoa Ciclosporine 1, 5 Citostátics 1, Digoxin 1 Ketoconazol 1, 5 Androgens 1, 8 Antiandrogens 1, 8 Estrogens, progesterone 1, 8 Colchicine, alopurinol Reduces fertilizing ability Sulfasalacine 1, 7, 5, afects sperm morphology Antiepiléptics 7 α-blockers 4, 7, relaxation blader neck Antipsicótics 1, 3, 7, 8 Tricíclics 1, 8, depletion dopamine β-blockers 1, 7 erectile dysfunction
1: Reduction of spermatogenesis
2: Decrease of libido
3: Delayed ejaculation
4: Retrograde eyjaculation
5: Inhibition testosterone synthesis
6: Reduction acrosome reaction
7: Reduction of motility
8: Pytuitary-gonadal axis
Product Mecanisms of action
Smoking and semen quality meta-analysis
14
Parameter Pooled mean difference P
IV* 95% CI
Semen volume -0.25 -0.32,-0.18 <0.00001
Sperm concentration -7.07 -10.03, -4.10 <0.00001
Total sperm count -32.20 -43.28, -21.11 <0.00001
Sperm motility -1.85 -3.27,-0.43 0.01
Normal morphology -4.92 -6.90, -2.94 <0.00001
IV: inverse variance
Li (Fertil Steril, 2011)
Spermatogenesis and alcohol consumption
15
0
10
20
30
40
50
60
70
<40 40 - 80 >80 - 160
Normal Arrest SCO
Pajarinen (Alcoholism Clin Exp Res, 1996)
Alcohol intake (grams/day)
% o
f te
sticula
r sam
ple
s
Alcohol and semen quality meta-analysis
16 Li (Fertil Steril, 2011)
Parameter Pooled mean difference P
IV* 95% CI
Semen volume -0. 30 -0.48, -0.13 0.0007
Sperm concentration 3.91 -8.32, 16.14 0.53
Total sperm count -5.02 -32.57, 22.52 0.72
Sperm motility -4.70 -23.20, 13.80 0.62
Normal morphology -1.68 -5.38, 1.66 0.30
IV: inverse variance
Effects of cannabis on reproduction
• In vitro effects (human) – Motility reduction/increased hyperactivation (biphasic effect)
– Impaired capacitation/acrosome reaction (through sperm receptors)
– Viability
– Mitochondrial activity
• Animal models – Impaired spermatogenesis (mitosis and meiosis)
– Teratozoospermia
• Clinical effects – THC blocks LHRH release and LH synthesis
– Dose-dependent reduction of testosterone
– Gynecomastia
– Symptoms of sexual dysfunction
– Oligozoospermia
17 Fronczak (J Androl, 2012)
Other drugs
• Opioids – Symptomatic hypogonadotropic hypogonadism
– Increased SHBG
– No specific studies on fertility
• Cocaine – Reduced sperm count
– Reduced motility in long term consumers (>5 years)
– Testicular effects in rats • Increased apoptosis
• Degenerating seminiferous tubules
• Reduced testicular blood flow
• Reduced pregnancy rates
• Methamphetamines, Ecstasy (animal models) – Reduced GnRH and testosterone
– Tubular apoptosis
– Sperm DNA damage
18 Fronczak (J Androl, 2012)
Diet and male infertility risk
• Conflicting reports on effects of fat intake
– Total fat: protective action on fertility (Serra-Magem, 2003)
– ω3 and linoleic: higher sperm concentratiion & motility (Christophe, 1998)
– Total saturated: lower sperm concentration (Attaman, 2012)
– ω3: higher normal morphology (Attaman, 2012)
– DHA in cftr mutant mice: Increase in sperm production (Álvarez, 2002)
• Other negative associations
– Yogur (Serra-Magem, 2003; Mendiola, 2009)
– Nuts, almonds, hazelnuts (Serra-Magem, 2003)
– Meat processed foods Mendiola, 2009
• Other protective associations
– Shellfish (Mendiola, 2009)
– Raw vegetables (Mendiola, 2009; Gaskins, 2012)
– Potatos, legumes (Gaskins, 2012)
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Exposure to environmental toxicants and sperm quality
20 Mendiola, RBM online (2008)
OR 95% CI exposure
Overall toxics and pollutants 6,9 2,2 – 21,4 past
Metals 9,6 2,1 – 45,7 past
Glues, solvents and silicones 10,4 2,6 – 42,5 current
Dust particles or fibres 12,9 1,5 – 109,3 past
Physical agents (heat) 4,7 1,1 – 19,2 current
Octylphenol
Nonylphenol
Polycyclic aromatic hydrocarbons
Bisphenol A
Polychlorinated biphenyls (PCB)
Lindane
Methoxychlor
Toluene
tert-Butyl hydroperoxide
Mono-(2-ethylhexyl) phthalate
Di-(2-ethylhexyl) phthalate
2,5- Hexanedione (2,5-HD)
1,3-Dinitrobenzene (1,3-DNB)
Nitrobenzene
Main environmental toxicants
RF-EMW, cell phones & fertility purported health consequences
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Differential effects of environment/lifestyle
22 Sharpe (Phil Trans R Soc, 2010)
Systematic screening of risk factors
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Concluding remarks
• Clinical Assessment – Need for full male assessment in all infertile men
– Active, systematic search for risk factors
– Support of psychological distress and symptoms
– Treatment of specific causes
– Attempt to modify correctable conditions
– Identification and follow-up of threats to health
• Research needs – Well designed prospective, comparative studies
– Development of tools to measure risk level
– Intervention studies to assess effects of modification/withdrawal
– Models to quantify interaction of multiple factors
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Cartagena, 340 08025 Barcelona. Tel. (+34) 934 169 700 Fax. (+34) 934 169 730 E-mail. lbassas@fundacio-puigvert.es
Thank you
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