Human Reproduction vol.6 no.8 pp. 1170-1175, 1991

OPINION

Environmental factors and fertility

W.Feichtinger Institut fiir Sterilitatsbetreung, Trauttmansdorffgasse 3a A1130 Wien and Second Department of Gynaecology and Obstetrics, University of Vienna Medical School, Vienna, Austria

This review deals with the decrease of male and female fertility during the last few decades which might to due to harmful environmental influences, stress and pollutants. Particular attention is drawn to the extent to which alcohol, coffee drinking, cigarette smoking and environmental pollutants may influence human fertility. Possible influences of increased radiation exposure after the nuclear accident of Chernobyl and possible hazards of electromagnetic fields are also discussed. Continuing research on the effects of environmental pollution on reproduction should be intensified and supported. Key words: causative factors/infertility/narcotics/organochlorine compounds/pollution

Introduction The effects of detrimental environmental influences on reproduction appear to have been proved and they are alarming. Infertility is defined as a failure to conceive while in a stable relationship and engaging in sexual intercourse without contraception for a period of 1 year or longer. We read in textbooks on gynaecology and obstetrics published in the fifties and the early sixties that at the time, 7 - 8 % of all newly-weds experienced this problem; today, however, we find 15-20% infertility in industrialized countries all over the world (Beier, 1988). The relevant figures in US publications from the 1970s were 8.5-15% (Bari-Kolata, 1978; McFalls, 1973). A recent estimate of the prevalence and incidence of infertility in a population, however, reports 2 0 - 3 5 % (Page 1989). In Europe, the figures vary between 10% (LeYidon, 1982) and 15-20% (Vessey et al., 1978; Howe etal., 1985; Rachutin and Olsen, 1982). Fundamental researchers in reproduction believe that harmful environmental influences, stress and pollutants are increasingly to be blamed for impaired reproduction in men and women and for damage to the earliest embryonic stages (Fischer, 1987; Beier, 1988). It is important that semen quality in general has gradually decreased over the period of time mentioned above (James, 1980). While a value of 60 x 106 spermatozoa per ml was considered normal in the fifties and sixties (Schirren, 1961), 40 x 106 per ml was regarded as a normal sperm count at the beginning of 1170

the seventies (Eliasson et al., 1970). According to the most recent criteria published in WHO, values down to 20 x 106 are today accepted as normal (Belsey et al., 1980). What then could be the cause(s) of the decrease of normal spermatogenesis in the male? It is difficult to answer this question, since, in contrast to female fertility, andrologists find aetiological causes for a 'poor' seminal analysis only rarely. It may, however, be assumed that 'stress factors' among others may reduce male fertility, similar to their effect on the female (McGrady, 1984; Lapple, 1990). Stress and infertility Stress at work, anger, worries, excitements, emotional strain, as well as the worries of involuntary childlessness and the compulsory mechanisms of family planning and their effect on sexual intercourse may all play a role here. Modern psychological test methods are able to detect trait anxiety and stress disposition, so that they can be correlated with hormone studies and clinical manifestations. The hypothesis that 'stress' and other disturbing influences, which might find expression in anovulation or hormonal imbalance (Nijs and Demyttenaere, 1989; Demyttenaere et al., 1989), may play an aetiological role in agreement with die familiar experience repeatedly found in the consulting room of infertility specialists, which is difficult to explain: such an experience is termed 'spontaneous healing'. It is a fact that 30% of all women who come for infertility counselling become pregnant during the informative phase of the therapy, before infertility treatment has begun (e.g. TVF waiting list pregnancies', Frydman, 1987; Dennerstein and Morse, 1988; Boulieu et al., 1990). A possible explanation may be that stress decreases after infertility counselling, because advice has been sought from those who know. Furthermore we have reports about spontaneous pregnancies after failure of an in-vitro fertilization (TVF) attempt, not only in cases of idiopathic infertility but, surprisingly, also in cases of impairments of the Fallopian tubes or even male infertility (Frydman, 1987; Boulieu et al., 1990; P.Kemeter and W.Feichtinger, unpublished observations). It is established that emotional stress may cause hyperprolactinaemia. This functional hyperprolactinaemia may explain the prolacrjn-producing pituitary microadenomas, which should be regarded as an adaptation to chronically enhanced function (Koninckx, 1978). The trend in modern fertility counselling is therefore to help couples in coping with their involuntary childlessness by biological and psychosocial consultation, which includes due © Oxford University Press

Environmental factors and fertility

consideration of all environmental factors, life situation and partnership. The success of integrated treatment of couples who undergo infertility therapy is not only measured by the pregnancy rate achieved; it is the objective of such a treatment to help couples with reproductive problems so that they may fully develop their creativity with or without children. Modern fertilization techniques confront the physician with the question to what extent he is a manipulator of fertility or a companion in distress (Kemeter, 1990). Alcohol, coffee drinking, cigarette smoking and fertility To begin, there is no question that chronic alcohol abuse affects semen quality and potency. The causes are the well-known internal secretory pathological changes, described, e.g. in liver cirrhosis, and the vitamin and trace element deficiencies common in alcoholics. Studies attempting to demonstrate the detrimental effect of ethanol on male fertility, carried out by semen analysis in patients with liver cirrhosis and incipient delirium, may therefore suggest wrong conclusions. An epidemiological study recently published in the USA (Marshburn etal., 1989) has, however, shown that regular alcohol consumption of ~ 40 g per day, even when continued over a lengthy period of time certainly does not have any negative effect on male fertility. Smoking of ^ 2 0 cigarettes per day, on the other hand, affects the ejaculate volume; smoking of >20 cigarettes per day affects the sperm count and also has a negative effect on sperm motility (Marshburn et al., 1989). The study also describes the influence of coffee drinking. Sperm motility was clearly better in non-smoking coffee drinkers (> four cups per day), while it was significantly reduced in smoking coffee drinkers (Marshburn et al., 1989). While the data may demonstrate effects on analysis of die ejaculate, these effects are irrelevant unless they can be shown to reduce the pregnancy rate in such patients; to my knowledge, no data are currently available on these matters. Alcohol consumption similarly relates to female fertility. Moderate alcohol consumption does not seem to represent a hazard to fertility; chronic alcoholism of addictive character, however, leads to a decrease of fertility as one of the features of general metabolic damage. It is also well known that chronic alcoholism may lead to fetal damage during the early stages of pregnancy and to alcohol embryopathies. There is also evidence that caffeine-containing beverages may decrease female fecundability (Wilcox etal., 1988). Married women who planned a pregnancy and who consumed four or more cups of coffee per day had only an 81 % chance of becoming pregnant per cycle compared to non-coffee drinkers. The risk of taking > 12 months to conceive was 80% greater for women with a high level of coffee intake than for non-coffee drinkers (Williams et al., 1990). Anodier study of 2817 women, however, showed no differences in the time to conception nor any association with caffeine consumption by women in 1818 infertile patients (Joesoef et al., 1990). Smoking clearly affects human reproduction (Stillman et al., 1986). Cigarette smoking during pregnancy is hazardous for the mother as well as the fetus. It is well known that the risk of miscarriage and perinatal mortality are increased in smoking women (Simpson, 1957; Rantakallio, 1978). Heavy smoking of

the father also more than doubles the risk of congenital malformations (Schmidt, 1986). Epidemiological studies have shown smoking women to reach the menopause at a lower age (Jick and Porter, 1977; Willet etal., 1983). Furthermore, pregnant as well as non-pregnant smoking women have lower oestrogen levels than non-smoking controls (MacMahon et al., 1982; Mochizuko et al., 1984). The reason for this is probably found in a selective inhibition of granulosa cell aromatase by constituents of tobacco smoke (Barbieri et al., 1986). Moreover, in this connection we must raise the question to what extent fertility is reduced when a women smokes. Is the desired conception more difficult or may it be delayed in women who smoke compared to non-smokers? Baird and Wilcox (1985) investigated whether fertility is reduced in smoking women, with 678 pregnant women in the USA. Thirty-eight per cent of nonsmoking women conceived during the first cycle, while only 28% of smoking women reported the same success. Moreover, a delay of conception for > 1 year was found three to four times more often in smoking women than in non-smokers. It is estimated that the fertility of smoking women is only 72% of the fertility of non-smokers. The fertility of women who smoked >20 cigarettes per day was considerably lower than that of women who smoked less. The study took into account age, number of previous pregnancies, previous medical counseling for fertility problems, frequency of sexual intercourse, type of contraceptive measures formerly taken, breastfeeding, alcohol consumption and body weight. We may therefore assume without doubt that cigarette smoking reduces the possibility of conception. It is also of interest that the chance of conception was not influenced by the smoking habit of the partner in this study. This contradicts the results obtained in other studies which found a negative influence of smoking on semen quality (see above). The study of Baird and Wilcox (1985) has shown that smoking must be added to the list of already known causes of reduced fertility. We have also investigated the effect of smoking on the success of IVF (Trapp et al., 1986). Although certain components of tobacco smoke were demonstrated in the follicular fluid (rhodanide), the substances apparently had no 'short-term' effect on the treatment carried out. It may be that the factors influencing the success of IVF are too complex to permit demonstration of the effect of specific noxious substances or pollutants. Narcotics, medicines and fertility A detailed discussion of the damaging effects that drugs evidently have on male and female fertility, either as side-effects or when abused, and of the influence of narcotics and of lesions during early pregnancy would go beyond die limits of this paper. Anaesthetics, for example, accumulate in the bodies of the members of the anaesthesia team and lead, as has been proved, to a higher rate of miscarriage in the young female members of these teams (American Society of Anaesthesiologists, 1974). Constant handling of cytostatics, whereby nurses for example inhale minute amounts, causes an increased rate of premature births (Selevan etal., 1985). Numerous drugs, narcotics, environmental toxic substances, heavy metals, etc may cause impotentia coeundi in men (Neumann, 1984; Bichier and Weckermann, 1986; Schill, 1986). 1171

W.Fefchtinger

Environmental pollutants and fertility Apart from smoking, consumption of coffee and use of drugs and narcotics, the contamination of the environment with persistent pollutants is of considerable importance. However, patients seen in the consulting room are still much more often affected by the former group of substances than by passive exposure to pollutants. An important distinguishing feature of toxic substances which are reproduction specific is their half-life. Organochlorine compounds for example are characterized by an extremely long retention time in fat and the tissue of liver, skin and muscles. They thus are persistent pollutants, which due to their lipophilic character and biological stability, accumulate in the nutritional chain. Many insecticides, fungicides, herbicides and polychlorinated biphenyls (PCBs) belong to this group. These substances are still widely used in agriculture and technology. One problem confounding the evaluation of toxic substances and their effect on human reproduction is multiple exposure. Tobacco smoke, for example, contains more than a thousand different compounds. This means that smoking represents a multiple exposure. The same is true of environmental pollutants. Workmen at the smelting furnace, for example, may be contaminated simultaneously by several heavy metals and the same is true of workers in chemical factories. Therefore, in most cases, it is impossible to describe the influence of individual toxic substances on fertility. So far, fertility disorders caused by toxic substances have been seen mostly only when the level of the dangerous substance was very high. The exposure of farmers who handle pesticides, for instance, may be higher than that of other people who are contaminated by organochlorine compounds only via the nutritional chain. An increased incidence of infertility and a reduced sperm count were seen in persons who had been in contact with the pesticide dibromochlorpropane (Whorton et al., 1977). After a poisoning episode in Japan, in which vegetable oil had been contaminated with PCB due to a technical defect, the levels of aldosterone and dehydroepiandrosterone were found to be elevated in the urine of male patients (Wassermann et al., 1979). Menstrual disorders and an increased incidence of risk pregnancies were seen in female patients (Yamashita, 1977). Ketone or decachlorketone is used as an insecticide and fungicide and oligozoospermia was diagnosed in workmen exposed to the substance (Whorton et al., 1977). Chlorinated hydrocarbons are also found in the tissue and blood of persons who are not exposed to these substances at their workplace or during accidents, the reason being the above-mentioned accumulation in the nutritional chain. So far there have been very few studies investigating the influence of such substances on human fertility. In a previous study, we have demonstrated the presence of the insecticides DDT, alpha-, beta- and gamma-hexachlorocyclohexane (HCH), and dieldrin, as well as the fungicide hexachlorobenzene (HCB) and PCBs in the follicular fluid of patients who wanted a child and were treated with IVF and embryo transfer. Forty-four samples of follicular fluid obtained from patients from the Federal Republic of Germany and 48 samples obtained from Austrian patients were examined for the presence of chlorinated hydrocarbons (Baukloh et al., 1985; Feichtinger 1172

et al., 1986). It was striking that significantly higher concentrations of HCH, DDT and dieldrin were found in the Austrian samples than in the Germans. Average PCB values were similarly higher in the Austrian patients. A direct effect of high concentrations of pollutants on IVF rates and implantation of the fertilized ovum was not demonstrated; however, there was a trend towards lower conception rates in the Austrian patients. Moreover, a group of five Austrian patients with very high levels of pollutants (PCB > 18 ng/ml) had a very low oocyte recovery rate from the follicles, i.e. 37% (as opposed to 86% in the rest of the study population). Animal experiments have shown that the intake of chlorinated hydrocarbons together with the feed may result in a considerable decrease of fertility (Allen, 1975; Lakkad et al., 1982; Lundberg, 1973; Reijnders, 1986) and it is also known that certain chemicals may destroy oocytes (Dobson and Felton, 1983; Mattison et al., 1983) in a similar way to radiation exposure. So far, however, it has not been possible to demonstrate whether rather high concentrations of chlorinated hydrocarbons in the ovarian follicle may direct affect primordial or developing oocytes. In a further study, semen samples from the partners of women who wanted a child and underwent IVF were investigated for the presence of the same toxic substances (Kerneter et al., 1986). The chlorinated hydrocarbons HCB, HCH and PCB were demonstrated in the seminal fluid in varying concentrations. There was no significant correlation between these concentrations and sperm count, motility and morphology. However, samples of the semen which had successfully led to fertilization and pregnancy after IVF/ET contained lower average concentrations of HCB and PCB than samples of semen which did not produce fertilization or pregnancy. HCH concentrations were not found to influence fertilization or the occurrence of pregnancy. Other studies (Wagner etal., 1989; Ensslen etai, 1990) partially confirmed our findings and found significantly higher concentrations of these toxic agents in patients with idiopathic infertility. A direct effect of chlorinated hydrocarbons and PCB on sperm motility was demonstrated recently by van der Ven et al. (1990) who observed a 10- to 20-fold higher accumulation of various chlorinated hydrocarbons in human cervical mucus compared to follicular fluid and seminal plasma. Furthermore, a significant reduction of sperm motility in cervical mucus was observed. Eggert-Kruse et al. (1990) found a similar effect of heavy metals on sperm—mucus interaction in vitro. These results furnish the first indications of a connection between the level of chlorinated hydrocarbons in the semen and reduced fertility. They demonstrate that these substances are present in the semen of men who do not know of or do not remember any contact with such substances. This was also the case in the majority of the men examined by us (Feichtinger et al., 1986). When prolonged contact with such substances is known, for instance in workers in a pesticide plant, subfertility may be more marked, and as described above (Whorton et al., 1977), sperm quality and fertility may be statisically lower in men who had had sustained contact with such substances than in men who had been exposed for a shorter period of time. These results should alert us and prompt us to pay more attention to environmental factors when studying subfertility in males in the future.

Environmental factors and fertility

The deterioration of ejaculatory parameters of white males which has taken place during the past 10—20 years and which was mentioned in the introduction to this paper, occurred predominantly in highly industrialized, Western countries and in Eastern countries with the highest degree of environmental pollution. We may therefore, as a working hypothesis, assume that environmental pollution plays an important role in human sub- or infertility. The following three factors may support such a hypothesis: first, man is the terminal link in the nutritional chain; second, environmental pollution is accepted in industrialized countries as a necessary evil; and third, the germinal epithelium is one of the most proliferative tissues of our body and therefore reacts with particular sensitivity to changes of the biological equilibrium. Fertility hazards of electromagnetic fields In recent times warnings have been heard repeatedly against possible influences of electromagnetic exposure due to the increasing use of computer and video display terminals, etc. The notion that video display terminals could be harmful was initially dismissed because of the minimal amount of ionizing radiation emitted by these devices. Recently, however, suggestions that weak electromagnetic fields are capable of interacting with biological systems have re-opened the debate (Delgado et al., 1982; MacKay, 1987). These and other issues were discussed at international meetings convened in London and in Sweden (Pearce, 1984; VDT News, 1986). Although the general consensus of the meetings was that neither ionizing nor electromagnetic radiation from video display terminals is likely to affect reproductive or other health outcomes and experimental display terminals are deemed electronically safe, ergonomic factors and stress associated with their use might contribute to the reproductive risk. Most needed at this time is experience gained by large-scale, carefully conducted epidemiological studies in order to establish whether or not a reproductive health problem exists (Goldhaber et al., 1988). This concern led to the initiation of a large-scale study in the United States, supported by the National Institute of Child Health and Human Development with a grant of two million dollars, the objective of which is to determine whether and to what extent visual display terminals represent a hazard to human reproduction. The study is being carried out by the Mount Sinai School of Medicine in New York on 8000 female office workers and it is intended to follow-up 800 women for a period of 1 year before and during pregnancy (Tompkins and McDonough, 1990). A pilot study performed at the Kaiser Permanent Medical Centre in California, which was similarly organized, has already demonstrated elevated miscarriage rates in women who work > 20 h a week at a computer terminal (Goldharber et al., 1988).

Radioactive fallout and fertility The possibility of germinal damage after radiation exposure, due to teramutagenic or teratogenic effects on gonocytes, embryos and fetuses has been known for a long time. Ionizing radiation may damage DNA molecules (as do cytostatics), alter or destroy genes and impair the form and number of chromosomes. Sterility,

infertility, intrauterine fetal death and malformations are potential effects of radiation (Fueger and Schreiner, 1985). The amount of radiation which will cause such damage is, as are all toxic effects, dose-dependent and rather high. A summation of high radiation doses over short periods of time must be considered probable, although the possibility of an additive effect of very small doses received over very long periods of time is at present scientifically controversial (Petkau and Chelak, 1976; Weihs and Gruber, 1983). As yet we have no unequivocal answer as to whether a threshold dose exists, since we can only inaccurately estimate the significance of repair systems after radiation exposure. In recent years and decades, especially following the disaster of the nuclear reactor at Chernobyl in 1986, we have learned much about environmental pollution by artificial radionuclides. Some of the long-lived substances, which accumulate in the nutritional chain, reach the human body in food and are deposited in different organs depending on their specific properties. The radiation exposure of cells and organs due to such incorporated radionuclides, as determined by the dose, is probably extremely low and in comparison with natural background radiation, theoretically perhaps even negligible. Despite the uncertainty about low dose effects, exposure to local artificial radionuclides over long periods of time should be avoided, especially where the particularly radiation-sensitive human gonocytes are concerned. In a recently published study, following the reactor accident of Chernobyl, we investigated the presence of radioactive caesium-134 (half-life 2—5 years) and caesium-137 (half-life 28 years) in the follicular and seminal fluids of couples seeking infertility treatment by IVF/ET (Krenn etal., 1990). Both radioactive isotopes were found in the majority of the samples; the levels of accumulation corresponded approximately to the values found in the milk of lactating mothers and in other tissues and body fluids. There was no statistical correlation between success of the treatment and the presence of radioactive nuclides in follicular fluid or semen. It must be admitted that such a correlation could probably not be expected in view of the rather short exposure time to radiation caused by incorporated radionuclides and in view of the above-mentioned complexity of this type of treatment. In a follow-up study (Barad et al., 1990), we demonstrated the presence of caesium, the only long-lived isotope, in a group of American patients. These findings, which in some cases were higher than those in the European patients, cannot be explained by the reactor accident of Chernobyl and are, in our opinion, indicative of an unknown, prolonged, chronic exposure perhaps involving nuclear bomb tests. It was striking that this group of patients could not be treated successfully and had no pregnancy in their history. The results obtained give rise to further investigations of follicular and seminal samples of patients from the USA, the Soviet Union and the Southern hemisphere. Concluding remarks The effect of environmental pollution on reproduction is now an important field for scientific research activity; the research gap, which evidently exists in this sector, is alarming and must 1173

W.Fekhtlnger definitely be closed. Basic research in reproductive biology has developed methods which can be applied for this purpose. However, research definitely needs further support, because the gap is still considerable. It would be desirable for all those who are politically responsible, in particular for health politics, to become increasingly conscious of the problem so that the healthy and effective reproduction of future generations can be guaranteed. References Allen^I.R. (1975) Responses of the nonhuman primate to polychlorinated biphenyl exposure. Research activities at regional primate centers. Fed. Proc., 34, 1675-1679. American Society of Anesthesiologists (1974) Occupational disease among operating room personnel: a national study. Am. Soc. Anesthesiol., 41, 321-330. Baird.D.D. and Wilcox,A.J. (1985) Cigarette smoking associated with delayed conception. / Am. Med. Assoc., 253, 2979-2990. Barad,D., Feinman.M., Cohen,B., Bartfai,G., Unfried,E. and Feichtinger.W. (1990) Radioactive cesium in follicular fluid and reproductive performance. 37th Annual Meeting of the Society for Gynecological Investigations, St. Louis, Missouri, Abstr., p. 220. Barbieri.R.L., McShane.P.M. and Ryan,K.J. (1986) Constituents of cigarette smoke inhibit granulosa aromatase. Fertil. Sterii, 46, 232-236. Bari-Kolata,G. (1978) Infertility: promising new treatments. Science, 202, 200-202. Baukloh.V., Bohnet.H.G., Trapp,M., Heeschen.W , Feichtinger.W. and Kemeter.P. (1985) Biocides in human follicular fluid. In Seppala.M. and Edwards,R.G. (eds), In Vitro Fertilization and Embryo Transfer. Ann. N.Y.Acad. Sci., 442, 240-250. Beier.H.M. (1988) Umweltbelastungen als Storungen der Fruhgraviditat und als Abortursache. GynOkologe, 21, 245-248. Belsey,M.A., Eliasson.R., Gallegos.A.J., Moghissi.K.S., Paulsen,M.R. and Prasad,N. (1980) Laboratory manual for the examination of human semen and semen cervical mucus interaction. WHO Press Concern, Singapore. BichJer,K.H. and Weckermann.D. (1986) Erektile Impotenz nach Trichlorathylenexposition. In Kxause,W. (ed.), UmwelteinflOsse auf die mdnnliche Fertilitat. Zuckschwerdt Verlag, Miinchen, pp. 97-101. Boulieu,D., Camus,H., Ayzac,L., Payan.F., Guerin,J.F., Lornage.J., Mathieu.C, Pinatel.M.C. and Regnier-Vigouroux,G. (1990) Grossesses spontanees chez les patientes en attente de fecondation in vitro. Contracept. Fertil. Sexual.. 18, 624-626. Delgado.J.M., Leal.J., Montegudi,J.L. and Gracia,M.G. (1982) Embryological changes induced by weak, extremely low frequency electromagnetic fields. J. Anal., 134, 531-533. Demyttenaere,K., Nijs.P., Evers-Kiebooms.G. and Koninckx,P.R. (1989) The effect of a specific emotional stressor on prolactin cortisol and testosterone concentrations in women varies with their trait anxiety. Fertil. Sterii., 52, 942-948. Dennerstein.L. and Morse,C. (1988) A review of psychological and social aspects of in vitro fertilisation. J. Psychosom. Obstet. Gynaecol., 9, 159-170. Dobson,R.L. and Felton,J.S. (1983) Female germ cells from radiation and chemical exposure. Am. J. Indust. Med., 4, 175-190. Eggert-Kruse.W., Rohr.G., Jochum.R., Adolph,M. and Runnebaum.G. (1990) Influence of heavy metals on sperm—mucus interaction in vitro. II. Joint Meeting ESHRE-ESCO. Milan. Hum. Reprod., 5 (Suppl. 1), Abstr. 158. Eliasson.G., Hellinga.F., Lubcke.F., Meyhofer.H., Niermann,H..

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