Gerhard A. Zielhuis

Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial

OBJECTIVE To study the effects of folic acid and zinc sulfate treatment on semen variables in fertile and subfertile men. DESIGN Double-blind, placebo-controlled interventional study. SETTING Two outpatient fertility clinics and nine midwifery practices in The Netherlands. PARTICIPANT(S) One hundred eight fertile and 103 subfertile men. INTERVENTION(S) Both groups were randomly assigned to receive one of four treatments for 26 weeks: folic acid and placebo, zinc sulfate and placebo, zinc sulfate and folic acid, and two placebos. Folic acid was given at a daily dose of 5 mg, and zinc sulfate was given at a daily dose of 66 mg. MAIN OUTCOME MEASURE(S) Before and after treatment, standardized semen and blood samples were obtained for determinations of sperm concentration, motility, and morphology according to World Health Organization guidelines; semen morphology according to strict criteria; and blood folate and zinc concentrations. Effects of the four interventions were evaluated separately in subfertile and fertile men. RESULT(S) Subfertile men demonstrated a significant 74% increase in total normal sperm count and a minor increase of 4% abnormal spermatozoa. A similar trend was observed in fertile men. Pre-intervention concentrations of folate and zinc in blood and seminal plasma did not significantly differ between fertile and subfertile men. CONCLUSION(S) Total normal sperm count increases after combined zinc sulfate and folic acid treatment in both subfertile and fertile men. Although the beneficial effect on fertility remains to be established, this finding opens avenues of future fertility research and treatment and may affect public health.

Male factor subfertility: possible causes and the impact of nutritional factors

OBJECTIVE To review possible causes for male factor subfertility with emphasis on nutritional factors such as zinc and folate. DESIGN A literature search was performed on MEDLINE and via bibliographies of published works. RESULT(S) Many causes for male factor subfertility are described in the literature. Both environmental and genetic factors could play a role. However, the pathogenesis of male factor infertility is poorly understood, including the role of specific micronutrients such as zinc and folate. Both zinc and folate are involved in the synthesis of DNA and RNA. Despite the fact that zinc deficiency leads to several clinical symptoms such as decreased spermatogenesis and impaired male fertility, the exact pathophysiology has not been clarified. CONCLUSION(S) Because most causes of male factor subfertility are unknown, more research is needed. Because male factor subfertility due to nutritional deficiencies is in principle amenable to curative and/or preventive action by supplementation, emphasis should be put on studies on the effect of specific nutrients on male fertility.

Pesticide exposure: the hormonal function of the female reproductive system disrupted?

Some pesticides may interfere with the female hormonal function, which may lead to negative effects on the reproductive system through disruption of the hormonal balance necessary for proper functioning. Previous studies primarily focused on interference with the estrogen and/or androgen receptor, but the hormonal function may be disrupted in many more ways through pesticide exposure. The aim of this review is to give an overview of the various ways in which pesticides may disrupt the hormonal function of the female reproductive system and in particular the ovarian cycle. Disruption can occur in all stages of hormonal regulation: 1. hormone synthesis; 2. hormone release and storage; 3. hormone transport and clearance; 4. hormone receptor recognition and binding; 5. hormone postreceptor activation; 6. the thyroid function; and 7. the central nervous system. These mechanisms are described for effects of pesticide exposure in vitro and on experimental animals in vivo. For the latter, potential effects of endocrine disrupting pesticides on the female reproductive system, i.e. modulation of hormone concentrations, ovarian cycle irregularities, and impaired fertility, are also reviewed. In epidemiological studies, exposure to pesticides has been associated with menstrual cycle disturbances, reduced fertility, prolonged time-to-pregnancy, spontaneous abortion, stillbirths, and developmental defects, which may or may not be due to disruption of the female hormonal function. Because pesticides comprise a large number of distinct substances with dissimilar structures and diverse toxicity, it is most likely that several of the above-mentioned mechanisms are involved in the pathophysiological pathways explaining the role of pesticide exposure in ovarian cycle disturbances, ultimately leading to fertility problems and other reproductive effects. In future research, information on the ways in which pesticides may disrupt the hormonal function as described in this review, can be used to generate specific hypotheses for studies on the effects of pesticides on the ovarian cycle, both in toxicological and epidemiological settings.

Smoking, Genetic Polymorphisms in Biotransformation Enzymes, and Nonsyndromic Oral Clefting: A Gene-environment Interaction

The importance of maternal smoking in the pathogenesis of oral facial clefts is not clear. Susceptibility to cigarette smoke depends on biotransformation of the toxic compounds by mother and embryo. In a population-based case-control study, we investigated the effects of maternal smoking during the first pregnancy trimester and the interaction with polymorphisms in the biotransformation enzymes cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase theta 1–1 (GSTT1) on the risk of nonsyndromic oral clefting in the offspring. We recruited 113 infants with nonsyndromic oral clefts and their mothers, as well as 104 control infants and their mothers. Maternal smoking habits were collected regarding the period 3 months before through 3 months after conception. Buccal swabs were taken from mothers and infants for genetic analysis. Maternal smoking was not strongly associated with oral clefting (odds ratio = 1.1; 95% confidence interval = 0.6–2.2), nor were CYP1A1 and GSTT1 polymorphisms. Mothers who smoked and carried the GSTT1-null genotype, however, had an increased risk for having a child with oral clefting compared with nonsmokers with the wild type genotype (odds ratio = 3.2; 95% confidence interval = 0.9–11.6). The risk was almost five times greater (odds ratio = 4.9; 95% confidence interval = 0.7–36.9) in mothers and infants both having the GSTT1-null genotype compared with both having the wild genotype. There was no interaction between CYP1A1 and maternal smoking in relation to oral clefting.

Fatigue and chronic fatigue syndrome-like complaints in the general population

BACKGROUND Most knowledge on chronic fatigue (CF) and chronic fatigue syndrome (CFS) is based on clinical studies, not representative of the general population. This study aimed to assess the prevalence of fatigue in an adult general population and to identify associations with lifestyle factors. METHODS Total 22,500 residents of Nijmegen were selected at random and interviewed by questionnaire. Data on 9062 respondents (43% response) were analysed, taken into account age, gender and concomitant disease. Subjects were classified into four groups: not fatigued (NF, reference group), short-term fatigue (SF, <6 months), chronic fatigue (CF, >or=6 months) and CFS-like fatigue (in accordance with the Center for Disease Control criteria for CFS, without clinical confirmation). RESULTS Our study population showed the following breakdown: NF 64.4% (95% CI 63.6-65.6%), SF 4.9% (95% CI 4.5-5.4%), CF 30.5% (95% CI 29.5-31.4%) and CFS-like fatigue 1.0% (95% CI 0.8-1.2%). Compared with the NF group, more of the CFS respondents were female [odds ratio (OR) = 1.9], obese (OR = 4.1), using analgesics (OR = 7.8), had a low alcohol intake (OR = 0.4), were eating less healthy food (OR = 0.5) and were physically less active (OR = 0.1). These associations largely applied to the SF and CF group. The fatigue could have been due to a concomitant disease in 34 and 55.5% of the SF and CF cases, respectively. CONCLUSION The prevalence of CF in the general population appears to be much higher than previously indicated. Even with strict criteria for CFS, it is estimated that approximately 1% of the adult population experiences this condition. Interestingly, a large part of this group remains unrecognized by the general practitioner. A striking similarity in lifestyle pattern between SF, CF and CFS calls for further research.

Teratogenic mechanisms of medical drugs

BACKGROUND Although prescription drug use is common during pregnancy, the human teratogenic risks are undetermined for more than 90% of drug treatments approved in the USA during the past decades. A particular birth defect may have its origins through multiple mechanisms and possible exposures, including medications. A specific pathogenic process may result in different outcomes depending upon factors such as embryonic age at which a drug is administered, duration and dose of exposure and genetic susceptibility. This review focuses on the teratogenic mechanisms associated with a number of medications. METHODS We used three methods to identify the teratogenic mechanisms of medications: the MEDLINE and EMBASE databases, two recent books on teratogenic agents and a list of drugs classified as U.S. Food and Drug Administration class D or X. Mechanisms were included only if they are associated with major structural birth defects and medications that are used relatively frequently by women of reproductive age. RESULTS We identified six teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis. Many medications classified as class X are associated with at least one of these mechanisms. CONCLUSIONS Identifying teratogenic mechanisms may not only be relevant for etiologic and post-marketing research, but may also have implications for drug development and prescribing behavior for women of reproductive age, especially since combinations of seemingly unrelated prescription and over the counter medications may utilize similar teratogenic mechanisms with a resultant increased risk of birth defects.

Cigarette smoking and the risk of male factor subfertility: minor association between cotinine in seminal plasma and semen morphology

OBJECTIVE To evaluate the impact of cigarette smoking on male factor subfertility and the semen parameters of sperm count, motility, and morphology by questionnaire and determination of the cotinine concentrations in blood and seminal plasma of fertile and subfertile males. DESIGN Case-control study of 107 fertile and 103 subfertile males who provided a standardized blood and semen specimen and completed a self-administered questionnaire about their smoking habits. SETTING Outpatient fertility clinic of the University Medical Centre St. Radboud, Nijmegen, The Netherlands. PATIENT(S) One hundred seven fertile and 103 subfertile males. INTERVENTION(S) Vena puncture and semen collection. MAIN OUTCOME MEASURE(S) Blood and seminal plasma cotinine levels in relation to semen parameters. RESULT(S) A higher frequency of cigarette smoking was observed in subfertile males than in fertile males, with an odds ratio of 1.7 (95% confidence interval, 0.9-3.2). The self-reported number of cigarettes smoked per day correlated with the cotinine concentrations in blood and seminal plasma for both groups. A small but statistically significant correlation was found between cotinine concentrations in seminal plasma and the percentage of abnormal sperm morphology, but not for other semen parameters (r(s) = 0.19). CONCLUSION(S) Although the mechanism of the toxicity of cotinine on sperm morphology is not clear, this study indicates only a minor effect of cigarette smoking on male factor subfertility, which is probably due to compounds in cigarette smoke other than nicotine (cotinine).

Hypospadias: risk factor patterns and different phenotypes.

Study Type – Aetiologic (case‐referent)
Level of Evidence 2a

Reproductive disorders among hairdressers

To evaluate whether hairdressers have an increased risk of reproductive disorders, we conducted a historical cohort study in the Netherlands. Because exposure to reproduction toxic agents in hair salons may have changed over time, we studied two specific periods: conceptions in 1986–1988 and in 1991–1993. We ascertained 9,000 hairdressers and, as a comparison group, 9,000 clothing salesclerks from their respective trade associations. All were of reproductive age in the defined study periods. Frequency matching on 5‐year age groups ensured comparability with regard to age. All women were approached by mail to complete a short, self‐administered questionnaire on reproductive history, including questions on time‐to‐pregnancy, spontaneous abortion, livebirths, and congenital malformations. In the analyses, we used random effect models to account for correlated outcomes (multiple pregnancies per woman). The results show that hairdressers who conceived in 1986–1988 had an increased risk of prolonged time‐to‐pregnancy of more than 12 months [odds ratio (OR) = 1.5; 95% confidence interval (CI) = 0.8–1.6], spontaneous abortion (OR = 1.6; 95% CI = 1.0–2.4), and a low‐birthweight infant (OR = 1.5; 95% CI = 0.7–3.1). In both periods, more major malformations occurred among children of hairdressers, but numbers were small. These results indicate an increase in reproductive risks for hairdressers in earlier years that now seems to be disappearing.

New evidence of the influence of exogenous and endogenous factors on sperm count in man.

OBJECTIVE To examine the association between individual exposures due to occupation, environment and lifestyle on sperm count, we conducted a case-control study among 92 fertile and 73 sub-fertile Caucasian males. STUDY DESIGN Data from questionnaires were analysed using simple univariate and multivariate logistic regression models. RESULTS At risk for oligozoospermia are men exposed to pesticides (odds ratio (OR) 8.4; 95% confidence interval (CI) 1.3-52.1), welding (OR 2.8; CI 0.9-8.7), antibiotic use (OR 15.4; CI 1.4-163), a history of mumps (OR 2.9; CI 1.3-6.7), gastrointestinal complaints (OR 6.2; CI 1.4-26.8), decreased intake of fruits (OR 2.3; CI 1.0-5.1), vegetables (OR 1.9; CI 0.7-5.0), or with female fertility disorders in their families (OR 8.4; CI 1.7-41.9). Unlike other studies, no associations were observed between oligozoospermia and exposure to paint or heat. CONCLUSION This study suggests new risk factors oligozoospermia in man and confirms previously reported results from others.