Cancer risk among parous women following assisted reproductive technology.

STUDY QUESTION: Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? SUMMARY ANSWER: Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. WHAT IS KNOWN ALREADY: Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. STUDY DESIGN, SIZE, DURATION: A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03- 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22-2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04-1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08-3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04-3.11). However, all findings became non-significant after correcting for multiple analyses. LIMITATIONS, REASONS FOR CAUTION: The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. WIDER IMPLICATIONS OF THE FINDINGS: In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. STUDY FUNDING/COMPETING INTEREST: The study was funded by the Norwegian National Advisory Unit on Women's Health. All authors claim no competing interests.

Expression of Bcl-2 family proteins and spontaneous apoptosis in normal human testis.

We investigated the frequency of spontaneous apoptosis and expression of the Bcl-2 family of proteins during normal spermatogenesis in man. Testicular tissue with both normal morphology and DNA content was obtained from necro-donors and fixed in Bouin's solution. A TdT-mediated dUTP end-labelling method (TUNEL) was used for the detection of apoptotic cells. Expression of apoptosis regulatory Bcl-2 family proteins and of p53 and p21(Waf1) was assessed by immunohistochemistry. Germ cell apoptosis was detected in all testes and was mainly seen in primary spermatocytes and spermatids and in a few spermatogonia. Bcl-2 and Bak were preferentially expressed in the compartments of spermatocytes and differentiating spermatids, while Bcl-x was preferentially expressed in spermatogonia. Bax showed a preferential expression in nuclei of round spermatids, whereas Bad was only seen in the acrosome region of various stages of spermatids. Mcl-1 staining was weak without a particular pattern, whereas expression of Bcl-w, p53 and p21(Waf1) proteins was not detected by immunohistochemistry. The results show that spontaneous apoptosis occurs in all male germ cell compartments in humans. Bcl-2 family proteins are distributed preferentially within distinct germ cell compartments suggesting a specific role for these proteins in the processes of differentiation and maturation during human spermatogenesis.

Seminal plasma lead, cadmium and zinc in relation to tobacco consumption.

The total quantity of zinc in the ejaculates of smokers was significantly lower than in non-smokers. This was not related to a significant increase in the quantities of seminal cadmium or lead, or to a decrease in sperm quality in the smoking group. It appears that tobacco consumption may have to exceed 20 cigarettes/day before a noticeable increase in seminal cadmium can be recorded. It is suggested that this reduction in zinc secretion may jeopardize the content of chromatin zinc, and thereby the stability of the sperm chromatin. This may then contribute to reproductive failure or have consequences for fetal development.

Concentrations of lead, cadmium and zinc in the tissues of reproductive organs of men.

The concentrations of lead in blood and the concentrations of lead, cadmium and zinc in tissues were determined in various reproductive organs, liver and kidney removed at necropsy from 41 men who had died suddenly. None of the reproductive organs specifically accumulated lead and no significant correlation could be demonstrated between blood and organ concentrations or between concentrations and age, occupation or urban/rural background of the subject. Unlike lead, the tissue concentrations of cadmium increased with increasing age in all of the reproductive organs examined. Of these, the epididymides and seminal vesicles contained the highest concentrations. Whereas prostatic zinc also exhibited a significant age-dependent increase, the concentrations in the testes declined with age. The age-dependent increase in testicular cadmium did not become apparent until after the fourth decade, when any potentially deleterious impact on male fertility has less relevance. It is concluded that measurable amounts of lead and cadmium are present in all of the human reproductive organs but their organ and age distribution do not offer strong support for their involvement in the aetiology of male infertility or in the genesis of glandular neoplasms.

Life styles of men in barren couples and their relationship to sperm quality.

This study is based on a questionnaire which focused on the possible association between life-style factors and male fertility in a group of 252 men attending our laboratory in connection with a fertility investigation. Their answers were correlated to sperm quality. No association could be documented between sperm quality and smoking habits, coffee drinking, a moderate alcohol intake, exposure to heat (sauna, hot baths, type of underwear, sedentary activities), or physical activities in their leisure time. In contrast, the reported average ejaculation frequency was significantly positively correlated to the motility of the sperm (% progressive), and inversely related to the proportion of sperm with abnormal morphology and semen volume. This indicates that the life style of the subject has little if any impact on semen quality, at least within the limits recorded in the present study.

Lifestyles of men in barren couples and their relationships to sperm quality.

This study is based on a questionnaire which focused on the possible association between lifestyle factors and male fertility in a group of 252 men attending our laboratory in connection with a fertility investigation. Their answers were correlated to sperm quality. No association could be documented between sperm quality and smoking habits, coffee drinking, a moderate alcohol intake, exposure to heat (sauna, hot baths, type of underwear, sedentary activities) or physical activities in their leisure time. In contrast, the reported average ejaculation frequency was significantly positively correlated to the motility of the sperm (% progressive) but inversely related to the proportion of sperm with abnormal morphology and semen volume. This indicates that the lifestyle of the subject has little, if any, impact on semen quality, at least within the limits recorded in the present study.

Cigarette smoking and human sperm quality assessed by laser-Doppler spectroscopy and DNA flow cytometry.

The sperm qualities of 350 men under fertility investigation were compared in relation to their smoking habits. The sperm variables included number, motility, morphology and vitality. Sperm motility was assessed objectively by laser-Doppler spectroscopy. In a randomly selected group, sperm samples were subjected to flow cytometry to assess the levels of DNA condensation. No significant differences (Kruskal-Wallis' test) in any aspect of sperm quality including DNA distribution could be demonstrated between non-smokers, moderate smokers (1-14 cigarettes/day) and heavy smokers (15-40 cigarettes/day). This was true when the data were pooled and when oligozoospermic/hypozoospermic ejaculates (1-39 x 10(6)/ml) and asthenozoospermic ejaculates (less than 25% of sperm cells with progressive movement) were analysed separately. The distribution of non-smokers, moderate and heavy smokers was the same in groups of men with normal sperm quality as those with impaired quality. The present study does not provide support for the contention that smoking has deleterious effects on sperm quality, at least using conventional parameters.

[Smoking and sperm quality in men undergoing fertility studies]. / Røyking og spermiekvalitet hos menn under fertilitetsutredning.

The sperm quality (sperm number, concentration, motility, morphology and vitality) of 350 men under fertility investigation were compared in relation to their smoking habits. No significant differences (Kruskal-Wallis test) in sperm quality could be demonstrated between non-smokers, moderate smokers (1-14 cigarettes/day) and heavy smokers (15-40 cigarettes/day). This was true when all the data were analyzed together and when analyzed separately for oligospermic/hypospermic men (1-39) or for men with reduced forward motility (less than 25% of sperm cells with progressive movement). The distribution of non-smokers, moderate and heavy smokers was the same in groups of men with normal sperm quality as in groups with reduced quality. The present study does not provide support for the contention that smoking has deleterious effects on sperm quality, at least when using conventional parameters.

Effects of oestrogen-induced hyperprolactinemia on the rat prostate.

Exposure of intact rats to increasing doses of oestradiol-17 beta in the presence of a constant amount of exogenous androgen caused a dose-related increase in the concentration of zinc in the lateral lobes and a decrease in the levels of ventral lobe prolactin binding. These changes occurred concomitantly with a dose-dependent increase in plasma prolactin levels, and could not be obtained in hypophysectomized rats given the same steroid treatment. In the intact animals a dose-dependent decrease in the responsiveness of the prostaglandin E1-dependent adenylyl cyclase in the ventral lobe was observed, an effect which has earlier been shown to be prolactin mediated. The results indicate that oestrogen has indirect effects on specific parameters of prostate function by inducing a relative hyperprolactinemia. This model may be useful in studying effects of chronically and physiologically elevated levels of endogenous prolactin on the rat prostate.