We observed an inverse association between TGCT and self-reported male pattern baldness and severe adolescent acne. The association with TGCT was most pronounced for increasing age at hair loss and frontal or temporal hair loss. Increasing rate of hair loss and increasing amount of hair loss were also inversely associated with TGCT. In histologic specific analyses, the associations were primarily limited to nonseminoma, however that could be due to insufficient sample sizes for the other histologic subtypes as the associations were in the same directions as those for nonseminoma. The reported associations were independent of known risk factors for TGCT, age, race and prior cryptorchidism, as well as income, an indicator of socioeconomic status.
In the literature, the role of androgen levels during adolescence and early adult life has received less attention than in utero
or early life exposures to estrogen. However to our knowledge, two studies have evaluated androgenic sex hormone correlates and TGCT risk (Depue et al., 1983
; Petridou et al., 1997
). In a case-control study of 97 incident TGCT cases and 198 age-matched controls in Athens Greece enrolled between 1993 and 1997, Petridou and colleagues reported an inverse association of TGCT with baldness as determined by the Hamilton-Norwood score (Petridou et al., 1997
). The authors reported that the inverse association with baldness was more pronounced among nonseminomas than among seminomas (Petridou et al., 1997
). Consistent with the findings of Petridou and colleagues, our results were supportive of an inverse association of nonseminoma, as well as overall TGCT, with increasing hair loss on the Hamilton-Norwood scale.
In a case-control study of 108 testicular cancer cases in men 16-30 years old and 108 age-matched neighborhood controls in Los Angeles County California, Depue and colleagues also reported an inverse association between TGCT and report of severe acne around the time of puberty (Depue et al., 1983
). The authors also collected information on the onset of puberty including age started shaving and age of voice change and found no association between TGCT and these factors; the authors did not report information on baldness or body size (Depue et al., 1983
). Our findings of an inverse association with severe acne but no association with onset of puberty are supportive of the results reported by Depue and colleagues.
It has been hypothesized that puberty may be a period of development during which exogenous or endogenous hormonal factors increase the risk of TGCT (Richiardi et al., 2007
). Hormonal exposures during this time may be more relevant to nonseminoma risk, given that the peak incidence of nonseminomas is ten-years earlier than the peak incidence of seminomas, and within a biologically relevant time period after puberty. However we cannot rule out the fact that we may not have seen an association between male pattern baldness and severe adolescent acne in the other histologic subtypes because of the limited sample size. It is plausible that increased androgen exposure, specifically 5-alpha-dihydrotestoterone (DHT), during puberty or early adulthood could potentially decrease risk of TGCT. The oily secretion of sebaceous glands is under the control of androgens; further, increases in androgen receptors and DHT production have been reported in patients with severe acne compared to normal subjects (Bonne et al., 1977
; Boudou et al., 1995
; Hay & Hodgins, 1974
; Sansone & Reisner, 1971
; Strauss et al., 1962
). Androgenic alopecia, the most common type of male pattern baldness, is characterized by recession of the hairline and is considered a part of the normal male secondary sexual characteristics (Hamilton, 1951
; Sawaya, 1999
). An absence of androgenic alopecia is observed in patients who lack 5 alpha-reductase, indicating that DHT, the 5 alpha-reduced metabolite of testosterone is the principle mediator of androgen-dependent hair loss (Balducci et al., 1996
; Hamilton, 1942
). Research has also shown that 5 alpha-reduced metabolites of testosterone are increased in balding areas of the human scalp (Sawaya & Price, 1997
). In human males, 5 alpha-reductase is expressed in the prostate, skin, epididymis, seminal vesicle and liver at high levels (Imperato-McGinley & Zhu, 2002
). Therefore it is plausible that the gonadal dysfunction contributing to decreased testosterone and increased DHT in men with severe acne or male pattern baldness may also contribute to decreased TGCT risk. It is also plausible that the onset of puberty may be programmed during the time period of organogensis. The puberty markers evaluated may therefore be proxy variables for exposures operating during the prenatal period.
Although our results are consistent with those of prior studies, there are several limitations to our study. The study relied on self-report, rather than measurement of baldness, severe acne, onset of puberty, height, weight and body build. It is possible that cases may more accurately or critically report these exposures; however, the bulk of these exposures were inversely associated with TGCT and thus case over-reporting is not likely to have occurred. Compared to trained observers, validation studies cited kappas of 0.47-0.55 for self-reported baldness (Littman & White, 2005
; Taylor et al., 2004
) and 0.48 for self-reported acne (Jagou et al., 2006
) suggesting that self-report of these features is quite reliable. The study evaluating the reliability of self-reported baldness using the Hamilton-Norwood scale also demonstrated that men’s self assessment of baldness at early ages was adequate (Littman & White, 2005
). The inverse association between balding and TGCT could have been related to hair re-growth after chemotherapy, especially if the age at onset of balding was close to the age of diagnosis/treatment. Further, if at the time of the interview those who experienced hair loss due to cancer treatment experienced difference in hair re-growth (curlier, coarser, color change) the cases might be more likely to report on current hair patterns rather than hair patterns prior to diagnosis. We examined the age at which balding reportedly occurred in the controls, and this age predated cancer diagnosis for the majority of cases in the matched sets (80.4%). In a sub-analysis restricting to cases with onset of hair loss reported at least two years prior to case diagnosis the inverse associations seen for all of the hair loss variables and TGCT risk were strengthened; suggesting that misclassification of hair patterns due to cancer treatment and hair re-growth did not substantially affect our results. It is likely that this study did not find an association between puberty onset and TGCT, because puberty onset in males occurs over a span of time and is not marked by one specific event, as a result there may be a large amount of variability with respect to the self-report of age at onset of puberty that contributes to the lack of association.
Controls, as a comparison group, are selected to represent the exposure distribution in the source population that gave rise to the cases. Whether friend controls provide this distribution is unkown and may be unlikely. Friend controls as the referent group in any study raises the concern that controls are too similar to cases, especially when considering behavioral exposures (cigarette smoking and alcohol consumption), as cases may nominate a friend control with similar behavior characteristics. If the friend controls in this study, in fact, are too similar to cases in terms of the exposures of interest, then it is likely that our estimates of risk would be underestimates of the true relationship between these factors and TGCT. In our study, however, the controls were older and reported higher incomes than cases, suggesting that over-matching was not present, at least for these factors. While we attempted to match on age, the cases tended to nominate friend controls who were generally older than they were, therefore as a matching factor, we adjusted for age in all of our analyses. We also adjusted for income as a potential confounding factor. Further the exposures we have examined, baldness, severe acne and indicators of puberty onset, are not behavioral factors and may be less subject to the bias described above. The specificity of our finding, that the association between male pattern baldness as well as severe acne and TGCT was primarily limited to nonseminoma, may be due to the limited numbers of seminoma and mixed germ cell tumors.
In summary, our findings of an inverse association between male pattern baldness and TGCT, particularly among men with nonseminoma, as well as, severe adolescent acne and TGCT are consistent with the findings of previous reports (Depue et al., 1983
; Petridou et al., 1997
). Increased endogenous androgen levels, specifically DHT, during puberty and early adulthood may directly affect TGCT risk by altering testicular development. Additional studies of endogenous hormone exposure during puberty and early adult life are warranted, especially studies evaluating the role of androgen synthesis and metabolism and the androgen receptor in TGCT.