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The association between undescended testis (cryptorchidism) and testicular cancer is established, but it is not known whether the risk of testicular cancer among men with unilateral maldescent is increased in both testes, or only on the undescended side. This is a meta-analysis of 11 case-control studies and 1 cohort study that all assessed the risk of testicular cancer separately for the undescended and descended testis. We used fixed-effects meta-analysis to calculate pooled estimates and 95% confidence intervals (CIs) for the relative risk. Of 199 tumors in men with unilateral cryptorchidism, 158 (79%) were on the ipsilateral side and 41 (21%) on the contralateral side. The pooled relative risks for testicular cancer in the ipsilateral and contralateral testis were 6.33 (95% CI, 4.30 to 9.31) and 1.74 (95% CI, 1.01 to 2.98), respectively. We conclude that in 1-sided undescended testis, the risk of testicular cancer may be increased in both testes, although to a much greater extent on the ipsilateral side., (Copyright (c) 2008 Wiley-Liss, Inc.)

Background: An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown., Objectives: Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors., Methods: We conducted a case-control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls., Results: A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6-13.3]. Boys born to obese [body mass index (BMI) > or = 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2-5.7) compared with boys born to mothers with a normal weight (BMI = 20-24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1-3.7) and 1.8-fold (95% CI, 1.2-2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1-53)., Conclusions: A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.

Objectives: It has been hypothesized that dihydrotestosterone (DHT), the main intracellular androgen in the prostate, affects prostatic tumour progression. In this study, we evaluated serum DHT levels at the time of prostate-cancer diagnosis in relation to survival., Methods: Sixty-five screening-detected patients diagnosed in 1988-1989 were followed for 15 yr. DHT levels at the time of diagnosis were determined through radio-immuno assay. Subjects were followed up through the nationwide tax register. Medical records of all dead subjects were reviewed, and cause of death was established by an endpoint committee. Data were analyzed through Kaplan-Meier estimation and Cox proportional-hazards regression., Results: Seventeen of 41 deaths in the cohort during follow-up were attributed to prostate cancer. Patients with DHT above the median had a significant better prostate-cancer-specific survival than those with DHT below the median (log rank p=0.0075). In the univariate analyses, one unit increase in DHT was associated with a hazard ratio (HR) of 0.14 (95% CI=0.02-0.93). In the multivariate model, including prostate-specific antigen level, the association between DHT and prostate-cancer-specific survival was not significant (HR=0.18; 95% CI=0.02-1.6). DHT level below the median remained significantly associated with decreased survival in the multivariate model (HR=0.23; 95% CI=0.06-0.90). No association was found between DHT level and hazard of dying from causes other than prostate cancer., Conclusions: Although the prognostic value of DHT levels at diagnosis remains unclear, these results provides evidence of an association between low DHT and decreased survival in prostate cancer patients.

Objective: Infertility is a common problem in women with hyperprolactinaemia. There are limited data on the fertility and pregnancy course among these women. The objective was to study parity, pregnancy and neonatal outcomes in women with hyperprolactinaemia as compared with a control group., Design: Register study., Patients: Two hundred and seventy-one female patients treated for primary hyperprolactinaemia were identified in the hospital record archives between 1974 and 2002. For each patient four comparison subjects, matched by sex, birth year and county of residence were identified in the Register of Population. Data were retrieved from the Swedish medical birth register and were analysed using logistic regression and analysis of variance. Measurements Parity, maternal age at first delivery, weeks of gestation, induction of labour, caesarean delivery, multiple birth, Apgar score, birth weight, length, sex, congenital malformations, neonatal care., Results: One hundred and sixty-two deliveries in the hyperprolactinaemia group and 1220 deliveries in the control group were analysed., Patients: with hyperprolactinaemia were significantly older at their first pregnancy than their controls: 29.0 (+/- 4.4) and 27.2 (+/- 4.8) years, respectively (P = 0.0002). Furthermore, parity was inversely associated with hyperprolactinaemia status (P for trend = 0.0009). The odds of having three or more children were threefold lower among the patients (OR 0.31 (95% CI 0.16, 0.60)). There were no differences between patients and controls with respect to pregnancy complications, delivery or neonatal outcome variables., Conclusions: We found no evidence of increased risk of pregnancy complications or adverse pregnancy outcomes in women with treated hyperprolactinaemia. However, the patients were older at their first pregnancy and had a reduced overall parity.

Germ-cell testicular cancer has a well-characterized descriptive epidemiology, whereas the aetiology remains largely unknown. It is believed that exposures acting prenatally are instrumental to germ-cell cancer development, although no specific exposure has been identified. Several epidemiological studies have investigated a number of indicators of prenatal exposures, such as birth order, gestational duration, birth weight, maternal age and nausea during pregnancy, but results are inconsistent. This paper briefly reviews the current support for genetic and environmental factors in testicular cancer aetiology. In particular, we have summarized the evidence suggesting a strong role of inherited susceptibility, which is probably carried by the effect of several unknown moderate-risk genes. We have illustrated inconsistencies in the previous studies on prenatal factors by estimating the heterogeneity and pooled odds ratios among twelve studies investigating the association between low birth weight and testicular cancer. We have discussed the possibility that puberty is another time window during which environmental factors may increase the risk of testicular cancer. Finally, we have reviewed the results from studies on cryptorchidism and impaired fertility in relation to risk for testicular cancer. In conclusion, we propose that future aetiological studies on testicular cancer should take postnatal exposures acting during puberty into account and, whenever possible, investigate both main effects and interactions among prenatal factors, genetic factors and postnatal factors.

Background: Undescended testis, which is a risk factor for testicular cancer, is usually treated surgically, but whether the age at treatment has any effect on the risk is unclear. We studied the relation between the age at treatment for undescended testis and the risk of testicular cancer., Methods: We identified men who underwent orchiopexy for undescended testis in Sweden between 1964 and 1999. Cohort subjects were identified in the Swedish Hospital Discharge Register and followed for the occurrence of testicular cancer through the Swedish Cancer Registry. Vital statistics and data on migration status were taken from the Register of Population and Population Changes for the years 1965 through 2000. We estimated the relative risk of testicular cancer using Poisson regression of standardized incidence ratios, comparing the risk in the cohort with that in the general population. We also analyzed the data by means of Cox regression, using internal comparison groups., Results: The cohort consisted of 16,983 men who were surgically treated for undescended testis and followed for a total of 209,984 person-years. We identified 56 cases of testicular cancer during follow-up. The relative risk of testicular cancer among those who underwent orchiopexy before reaching 13 years of age was 2.23 (95% confidence interval [CI], 1.58 to 3.06), as compared with the Swedish general population; for those treated at 13 years of age or older, the relative risk was 5.40 (95% CI, 3.20 to 8.53). The effect of age at orchiopexy on the risk of testicular cancer was similar in comparisons within the cohort., Conclusions: Treatment for undescended testis before puberty decreases the risk of testicular cancer., (Copyright 2007 Massachusetts Medical Society.)

For no apparent reason, the incidence of testicular cancer has increased to epidemic proportions in many countries. Pregnancy smoking has been suggested to be a cause. Previous analytical studies have been negative, but the inherent difficulties in retrospective assessment of this exposure have led to no definite conclusion. We have conducted a population-based case-control study on 192 cases of testicular germ-cell cancer-born in Sweden in 1973 onwards and aged >/=15 at cancer diagnosis-and 494 matched controls, where data on maternal smoking were collected during pregnancy. We found no association with testicular cancer for maternal smoking during pregnancy (OR, 0.91; 95% CI, 0.64-1.30), and there was no evidence of a dose-response effect. We conclude that the epidemic rise in testicular cancer in many populations is not due to the surge in smoking among women., ((c) 2007 Wiley-Liss, Inc.)

Objective: The purpose of this study was to study the effect of pregnancy outcomes on risks of continued smoking in subsequent pregnancy., Study Design: Cohort study of first and second single births among 98,778 Swedish women who were daily smokers in first pregnancy., Results: In all, 70.2% of women continued to smoke in second pregnancy. Compared with women with a previous normal pregnancy outcome, risk of smoking in second pregnancy was increased among women with a previous small-for-gestational-age birth (adjusted odds ratio [OR], 95% CI 1.28 [95% CI 1.19-1.37]), and reduced among women who had experienced a stillbirth (OR 0.76 [95% CI 0.63-0.93]) or an infant death because of congenital malformations (OR 0.67 [95% CI 0.49-0.92]. A previous preterm birth, Sudden Infant Death Syndrome, and other causes of infant death did not influence risk., Conclusion: A previous adverse pregnancy outcome has only a modest influence on smoking habits in the successive pregnancy.

Objective: Patients with testicular cancer have decreased fertility prior to the diagnosis of cancer, although it is not clear whether the subfertility is the result of an emerging tumor, or whether subfertility and testicular cancer share causes. To test if they share causes, we assessed fertility among brothers of patients with testicular cancer., Methods: We compared 5,613 siblings (2,878 brothers) of patients with germ-cell testicular cancer, diagnosed in Sweden from 1960 to 2002, with 6,151 population controls (3,202 men). Using the Swedish Multi-Generation Register, we obtained information on the number of children born (until December 2003) from cases (n = 9,480) and controls (n = 10,739). Fertility was measured using two indicators, (a) offspring twinning rates, as dizygotic twinning is reduced by male subfertility, and (b) number of children. We used unconditional logistic regression, and analyzed brothers and sisters separately. Analyses on the number of children were restricted to subjects (39%) born prior to 1954, for whom information on reproductive life until age 50 was available., Results: Brothers, but not sisters, of patients with testicular cancer were less likely to have unlike-sex twins than controls (for unlike-sex twins, the odds ratio for the father being a sibling of testicular cancer patient was 0.53; 95% confidence interval, 0.26-1.09). The likelihood of being a brother of a patient with testicular cancer decreased monotonically with increasing number of children (P = 0.05), whereas no association was observed for the sisters., Conclusion: The decreased fertility found among brothers of patients with testicular cancer argues in favor of shared causes between cancer-associated subfertility and testicular cancer. Genetic links and shared environment could explain the association.

Objective: To characterize women with hyperprolactinaemia at diagnosis and to assess the effect of treatment after long duration of the disease., Design: Retrospective chart review., Patients and Measurements: Two hundred and seventy-one women with hyperprolactinaemia at the Karolinska University Hospital, Stockholm, Sweden between 1974 and 2002 were evaluated retrospectively. Criterion for inclusion was elevated S-PRL (> or = 20 microg/l) found on at least two occasions. Secondary hyperprolactinaemia was excluded. The patients were followed for a median time period of 111 (6-348) months. Two hundred and forty patients were treated with dopamine agonists, 17 underwent surgery, seven received radiotherapy and seven were followed without treatment., Results: Mean age at diagnosis was 31 (+/- 9.5) years and median PRL level was 72 (25-3500) microg/l. Menstrual disturbances were present in 87% of the women of reproductive age and 47% had galactorrhoea. Microadenomas were found in 63%, macroadenomas in 8% and idiopathic hyperprolactinaemia in 29%. Patients with menstrual disturbances had higher PRL levels than women with normal menstrual function (P < 0.001). We found no differences in PRL levels between patients with or without galactorrhoea (P = 0.578). At the end of clinical follow-up, menstrual cycle was normalized in 94% and galactorrhoea disappeared in 94%. In the medically treated patients, median PRL levels decreased from 70 (25-3100) to 13 (0-89) microg/l, (P < 0.0001). Normalization of PRL level was achieved in 71% of the patients and 80% showed a total or partial degree of tumour shrinkage. In the surgically treated patients, 53% had normal PRL levels without medication at follow-up., Conclusion: Medical treatment was effective in correcting hypogonadism, normalizing PRL levels and reducing tumour size in the majority of the patients after short-term treatment and also in the long run. However, the possibility of transsphenoidal surgery in specific cases must be considered.

Androgens are believed to play a major role in the etiology of prostate cancer, but studies of sex-hormone exposure in relation to risk for prostate cancer have been inconclusive. Male fertility may be an indicator of long-term androgen status. To study the role of testicular function in prostate cancer development, we have assessed number of biological children in relation to risk for this malignancy. We carried out a population-based case-control study with retrospective ascertainment of cases occurring in Sweden between 1958-98. In total, 48,850 cases of prostate cancer were identified through the nation-wide Cancer Registry. For each case, one control, matched by year of birth, was randomly selected from the Swedish population. Information on offspring was obtained from the Swedish Multi-Generation Registry. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between number of offspring and risk for subsequent prostate cancer. Being childless or having fathered one child only were associated with reduced risks for prostate cancer compared to having fathered 2 or more children (OR = 0.83; 95% CI = 0.81-0.86 and OR = 0.93; 95% CI = 0.90-0.96, respectively). There was no further change in risk associated with fathering of more than 2 children. The risk for prostate cancer is reduced among childless men. A dysfunctioning reproductive apparatus fueling to a lesser extent prostatic growth, could be a plausible mechanism of this association., (Copyright 2005 Wiley-Liss, Inc.)

Previous studies have suggested an association between subfertility and testicular cancer by using fecundity and semen characteristics to measure fertility. The occurrence of twinning in offspring may be used to investigate male reproductive health, because dizygotic twinning is reduced by male subfertility. We therefore assessed number of children and offspring twinning rates among 4592 Swedish patients with testicular cancer and 12 254 control subjects. Before diagnosis, case patients had a decreased number of children (for testicular cancer, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.62 to 0.81; at least three children compared with no children), with a lower frequency of dizygotic twinning (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P =.03, two-sided Wald test). We also found an increased occurrence of twinning after diagnosis, probably attributable to treatment for iatrogenic subfertility. Our study strongly supports evidence of an association between subfertility and the subsequent risk for testicular cancer.

Although the incidence of testicular cancer is increasing, substantial differences in incidence between countries and populations exist. These differences cannot be explained solely by genetic differences, but environmental exposures, particularly early exposures, have been implicated in the etiology of testicular cancer. To assess whether early exposures contribute to the incidence of testicular cancer, we identified 93 172 Finnish men who immigrated to Sweden between 1969 and 1996 and followed them for the occurrence of testicular cancer. The risk of testicular cancer was lower for Finnish immigrants to Sweden than for the Swedish general population (standardized incidence ratio [SIR] = 0.34, 95% confidence interval [CI] = 0.21 to 0.53). The reduced risk was associated with both seminomas and non-seminomas. Neither age at immigration nor duration of stay in Sweden had any impact on the reduced risk. Although the type of environmental exposures remains unknown, the results strongly indicate that early exposures are major determinants for testicular cancer.

It has been hypothesized that smoking during pregnancy could increase the offspring's risk for testicular cancer. This hypothesis is indirectly supported by both ecological studies and studies of cancer aggregations within families. However, results from analytical epidemiological studies are not consistent, possibly due to methodological difficulties. To further study the association between smoking during pregnancy and testicular cancer, we did a population-based cohort study on cancer risk among offspring of women diagnosed with lung cancer. Through the use of the Swedish Cancer Register and the Swedish Second-Generation Register, we identified 8,430 women who developed lung cancer between 1958 and 1997 and delivered sons between 1941 and 1979. Cancer cases among the male offspring were then identified through the Swedish Cancer Register. Standardized incidence ratios were computed, using 95% confidence intervals. We identified 12,592 male offspring of mothers with a subsequent diagnosis of lung cancer, and there were 40 cases of testicular cancer (standardized incidence ratio, 1.90; 95% confidence interval, 1.35-2.58). The association was independent of maternal lung cancer subtype, and the risk of testicular cancer increased stepwise with decreasing time interval between birth and maternal lung cancer diagnosis. Our results support the hypothesis that exposure to cigarette smoking in utero increases the risk of testicular cancer.

To assess the association between adult body size and germ-cell testicular cancer risk and to understand whether this association is independent from perinatal characteristics, a nested case-control study was conducted. Three hundred and seventy-one patients with testicular cancer, registered in the Swedish Cancer Registry between 1958 and 1996 and aged 20-54 years at diagnosis, and 1238 individually matched controls were identified. Information on adult body size at age 18 years was obtained for all subjects through the Military Service Conscription Register, whereas perinatal information was obtained through birth records at the subjects' respective maternity wards. Height was positively associated with testicular cancer risk, and the association persisted after taking into account perinatal characteristics. The adjusted odds ratio (OR) was 1.55 [95% confidence interval (CI), 1.10-2.17] for the third tertile of height as compared with the first. No association between the risk for testicular cancer and body mass index was found. Long duration of gestation was negatively associated with testicular cancer risk [OR = 0.64 (95% CI, 0.45-0.91), post-term compared with term], whereas high birth weight appeared to increase the risk [OR = 1.35 (95% CI, 0.99-1.85)]. In conclusion, adult height and perinatal factors acted independently, suggesting that both the fetal life and the childhood and adolescence periods are windows of susceptibility to exposures that influence the risk for testicular cancer.