Association between male pattern baldness and testicular germ cell tumor: a meta-analysis

Male pattern baldness, also known as Androgenetic alopecia (AGA), is an inherited pattern of baldness hormone-regulated by the testosterone metabolite dihydrotestosterone characterized by follicular androgen sensitivity and follicular miniaturization [1]. While inhibition of Dihydrotestosterone (DHT) production slows the progression of male pattern baldness (MPB) [2]. The onset of androgenetic alopecia is extremely variable, and appears to be determined by the presence of sufficient circulating androgens and the degree of genetic predisposition. And also androgenetic alopecia is a polygenic mode of Inheritance [1]. Moreover, its frequency increases with age and affects up to 80% Caucasian men and 42% of women [3]. AGA is a common disorder affecting almost 50% of men throughout their lifetime [4] androgen status does not decline with aging among older men who remain in excellent (asymptomatic) health [5]. So, We have the reason to believe that AGA plays an important role in the pathomechanism of some androgen related tumors in men. AGA shares a substantial biological basis with numerous other human phenotypes [6]. This may have major implications in terms of the evaluation of MPB as an early prognostic marker for different phenotypes such as prostate cancer(PC), sudden cardiacarrest or neurodegenerative disorders. Testicular cancer is a relatively rare tumor representing < 2% of all malignancies in men. Nevertheless, it is the most common tumor among young males in Europe and North America [7] the only well-documented risk factors are cryptorchidism, prior history of TGCT, and family history of TGCT [7]. The fact that testicular cancer is hormone-dependent is supported by its rapid increase in incidence starting at pubertal age. In addition, late age at puberty has been inversely associated with the risk of testicular cancer [3]. In androgenetic alopecia, hormonal signals lead to change in genes regulating hair follicle size and cycling and there is a gradual diminution of the hair follicle [8]. AGA and testicular cancer share some biological and epidemiologic risk factors: aging, genetics inheritance, and androgenetic influence. Although Liang et al. [9] conducted a meta-analysis to reveal the relationship between AGA and testicular cancer in 2018,we analyzed the data about the risk of testicular cancer from a new case-control study reported by Lee et al. [10] that men with AGA may not be associated with testicular cancer. This current analysis we obtained is different from the previous statistic result reported by Liang et al. [9].

As a result, we conducted a systematic review and a comprehensive meta-analysis in order to further investigate the issue and identify potential sources of heterogeneity that might be confounders that have affected some existing conclusions.

This systematic review and meta-analysis involved a total of 884 cases from 5 observational studies [10, 14‐17]. Our study included the largest sample as far as we know. From the comprehensive data we analyzed, we concluded that men with any pattern baldness may decreased the risk of testicular cancer, which means that AGA could be a protective factor in the cancer of testicle. In the subgroup between the type of baldness, we discovered man with AGA at grade 2(II) may have less risk than other stages, In addition, we found that there was no significant relationship between types of testicular tumor and AGA. Before we did our study, a systematic analysis of the relationship between alopecia and testicular cancer had been discussed. That mata-analysis included 4 case-control reports from 1997 to 2016 which reported that man with baldness could have less risk of testicular cancer compared with no baldness. And they found that baldness is significant inversly related with nonseminoma. However, from the recently report by Lee et al., we could not see any obvious connection between baldness and the risk of TGCT. The mechanism of alopecia in the risk of testicular cancer is still unclear. While in another discussion about the association between AGA and prostate diseases, especially prostate cancer which has been studied thoroughly, in Zhou et al’s study [18], which included 1138 incident prostate cancer cases, they concluded that men with frontal plus moderate vertex baldness at age 45 years has an increased risk of aggressive prostate cancer. This result provided evidence that we have reason to believe that hair loss is associated with male reproductive system tumors. In Petridou et al. [14] research,they had studied different factors on the risk of testicular cancer including age,body mass index, baldness, height and so on. Among these factors,they discovered a conclusion that Baldness is inversely associated with testicular cancer (p = 0.04). This was the first time that baldness had been linked to testicular cancer in a case-control study. However,in this study report,it had some limitations, including that it only considered the relationship between different types of alopecia and testicular cancer,but not included the subtypes of testicular cancer were not presented. In Farzana et al. [15], they found that no significant association between baldness and this cancer, and also found that seminoma, which has a known older age at diagnosis than nonseminoma. In Trabert et al. ‘s report [16], they got same result comparied with Petridou [14] and Farzana [15], in addition, their findings of inversly association between baldness and testicular cancer, especially among men with nonseminoma, which conflicted with Moirano et al’s report [17] that this association between AGA and TGCT was more stronger among seminoma. so we still need a large number correlation studies to clarify the relationship between hair loss and testicular cancer. Besides the male pattern baldness, there might be some related factors which are significantly related with testicular cancer,like race, age, Body Mass Index (BMI), young adult African Americans who have higher levels of circulating testosterone than their white counterparts [19], according to Depue et al. [20] they got the insight that severe acne at puberty, which is thought to reflect increased levels of androgens, was inversely associated with the risk of testicular cancer. So, we can consider African Americans may have a lower risk of testicular tumor. As far as we concerned, as proxies for high androgen levels or high androgen sensitivity, alopecia and acne require a deeper understanding of the mechanisms of androgen action and its impact on testicular cancer. AGA could be used as a signal for sex hormone metabolism, hormone secretion and human androgen sensitivity. Men with AGA have higher levels of dihydrotestosterone within the hair follicles and its blockage helps to slow the progression of baldness [21]. It has been hypothesized that puberty maybe a period of development during which endogenous hormonal factors increase the risk of TGCT [22], It has been reported that circulating testosterone, DHT, and E2 declined gradually during male aging [8]. androgen activity through multi-step signaling process in pathophysiology of AGA [23]. In addition, androgen receptor and androgen metabolic pathway genetic variation studies showed that Ser312-Asn polymorphism of the luteinizing hormone receptor was linked to an decreased relative risk of TGCT [24]. These findings provide sufficient evidence for the effect of AGA on testicular cancer.

In the similar study reported by Liang et al. [9], we got the same result that AGA exposure is inversely related to the risk of TGCT and men with 2nd stage baldness could have lower incidence of testicular. However,about the histological subgroup, we got no closed relationship between AGA and type of testicular cancer, this is in conflict with the view authors had mentioned that the inverse relationship was more predominant among nonseminoma with less heterogeneity. And also,in another report written by Lee et al. [10], we did not find a link among hair loss and testicular cancer, although they analyzed a large number of cases.From these related studies, we have suggested that hormonal related factors was significantly inversely related to the risks of TGCT. However, because of the low incidence of testicular tumors in the population, we do not have sufficent case to analyze, which may limit our results. In addition, other factors like race, age, hight also affect the heterogeneity.

As an important organ that maintains male charecteristics, the human testes are prime targets for hormonal modulation. We found evidence of association between AGA at any age and a significant decreased risk of testicular cancer based on meta-analysis of case-control studies,in histological subgroup analysis, we explored that the second level of hair loss is more benificial for reducing the risk of TGCT. This conclusion may suggest that AGA or men with baldness may be the protective factor for the TGCT. AS far as we concerned, our study includes only 5 case-control reports and there are some divergent views in these documents. Further andomized controlled trials studies should be required to confirm the potential relationship between AGA and TGCT.