Our large case–control study has shown a clear, statistically significant, association between reported diagnosis of male infertility and risk of breast cancer, and this was supported by analysis of numbers of offspring—there were significantly more men with no children among cases than among controls, both overall and after excluding potentially confounding conditions, and in analyses restricted to married men.
Case–control studies are notoriously at risk of bias, but there seems no plausible reason why our infertility results should have been artefactual. Although our controls, unlike the cases, were not strictly population-based, because of the poor response rate now for population-based controls [16, 17], they were drawn from the whole country and age range of the cases, we adjusted for the difference in distribution of relevant variables between the cases and controls, and the infertility results were present in comparisons with each of the two control groups, from different sources, used in the study. The association with infertility is not one plausibly known to the subjects, and there is no obvious reason why the men should have recalled or reported it in a way biased between cases and controls, especially for reporting of number of children. We could not interview patients who died before they could be approached or interviewed, which could lead to bias if survival was related to infertility, but there is no obvious reason why it should be nor any evidence for such an association to our knowledge. Although a small part of the association is explicable by the known association of male breast cancer with Klinefelter syndrome [21], this is far too rare to account for the overall relation, which persisted after excluding subjects with known Klinefelter, based on cytogenetic karyotyping of the first 901 cases and self-reporting of diagnosis for the remainder. The association also largely remained after additional exclusion of patients with other pre-existing potential confounders, namely severe obesity, past malignancies that can be treated with chest radiotherapy, and testicular abnormalities [22]. It is arguable, however, whether the latter exclusions are overly conservative, since several of the testicular conditions, which were the main exclusions, may have been diagnosed as a consequence of investigations for infertility rather than diagnosed independently of it: we did not have information to determine the sequence of diagnostic dates. There are several other factors that are known or posited to be related to risk of infertility, including diabetes, dyslipidaemia, cirrhosis of the liver, alcohol consumption, smoking, and endocrine disrupting chemicals [7], but there is no convincing evidence that these factors are related to risk of breast cancer in men [2, 8,9,10,11,12,13,14,15, 23], and hence, no reason to believe that they are confounders for which adjustment would be needed in our infertility analyses. Conversely, known risk factors for breast cancer in men, family history of breast cancer and risk genotypes [1] are not known to be associated with risk of infertility and hence again are not clear confounders. Nevertheless, in sensitivity analyses, adjustment for those of these variables for which we had data made no material difference to the results.
Self-reported fertility is a ‘soft’ measure with potential for misclassification for several reasons. Infertility is a complex process that can include factors from both the male and female members of a couple; men may not report (or even know of) children born outside marriage; they may have remained childless by choice, not infertility; and they may report a low sperm count even if it was not the reason for infertility. Additionally, the self-reports were reliant on the men’s recall and understanding—the evidence would have been stronger if infertility could have been validated from medical records, but this was not practical across an entire country over many decades. However, although all of the above sources of misclassification might plausibly have led to dilution and hence underestimation of any true risks, there is, as noted above, no obvious reason why this should have been differential between cases and controls, and hence have led to bias.
The lack of a significant association of male breast cancer with infertility in most of the previous literature does not argue substantially against the association that we found: the few published studies [8,9,10] have had mixed results, with at most only 227 cases of whom 7 reported infertility [8]. A pooled analysis that included 420 cases [2] found a non-significant odds ratio of 1.36, although based on heterogeneous case–control studies with heterogeneous definitions of infertility that complicate interpretation, and with analysis solely of a dichotomy between “history of infertility” and no such history.
Our finding of greater risk for men with no biological children compared with any children is congruent with infertility as a risk factor. Most previous studies have not found such an effect, but based on very small numbers [11, 12, 15, 24], although one small study [13] (21 cases) and a pooled analysis [2] found significantly raised risk for men with no children.
We found significantly decreasing risk with increasing numbers of children. However number of children beyond one is difficult to interpret as an indicator of male fertility, since it may more reflect social and cultural factors than fertility per se. The same is true for age at first birth. Similarly, it is difficult to interpret analyses confined to married men because of the changing relation of marital status to fatherhood in Britain, such that the meaning of ‘married’ in relation to potential for fatherhood has changed over time. Before 1980, 10% or fewer of births in England and Wales were outside marriage, but the proportion has since soared such that by 2000, 40% were outside marriage and subsequently almost 50% [25]. In our main analyses, we adjusted for marital status; in comparison, analyses confined to married men showed slightly less marked odds ratios, but entirely in the same direction.
Our data showed that the association of infertility with male breast cancer risk was clearly present for invasive tumours, but not significant, based on much smaller numbers, for in situ tumours: this does not appear to have been investigated previously.
The reason for the association of male infertility with breast cancer risk demonstrated in our data is uncertain. Infertility can result from a wide range of factors, including genetic, congenital anomalies of the genitourinary tract, other anatomical reasons, and sexual dysfunction, but most cases are idiopathic [22].
The main source of testosterone secretion in men is the testis, so one potential link between infertility and breast cancer risk would be via hormonal effects of testicular abnormalities. For instance, mumps orchitis can lead to testicular atrophy and long-term reduced testosterone production [26], and can lead, albeit not commonly, to subfertility or, rarely, sterility [27]. Although significant associations remained (albeit slightly reduced) after exclusion of men diagnosed with testicular abnormalities that have been reported to be associated with breast cancer risk, it is possible that associations remained from other abnormalities of the testes not know to be risk factors, or more subtle abnormalities that would not receive a diagnosis.
It has been hypothesised that prenatal oestrogen exposure can lead to raised risk of male infertility [28], in which case a possible connection would be if the prenatal hormone environment might also affect male breast cancer risk, as hypothesised for women [29].
