1

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

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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

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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

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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

21

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