Department of Growth and Reproduction and EDMaRC, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
Department of Oncology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
Hum Reprod. 2021 Aug 18;36(9):2443-2451. doi: 10.1093/humrep/deab162.
Is anogenital distance (AGD) shorter in testicular cancer (TC) survivors than in men from the general population, and is AGD affected by testosterone replacement therapy in adulthood?
AGD, measured as distance from anus to scrotum (AGDas), is shorter in TC survivors and does not change as a result of testosterone replacement therapy.
Animal studies have shown that AGD is a postnatal 'read-out' of foetal androgen action, and short AGD in male offspring is considered a sign of feminization caused by in utero disruption of the reproductive system. Likewise, measurement of AGD in human studies has suggested AGD to be part of the testicular dysgenesis syndrome hypothesis, which proposes that male reproductive disorders, such as hypospadias, cryptorchidism, some cases of impaired semen quality and TC, all share a common foetal origin.
STUDY DESIGN, SIZE, DURATION: The aim was to assess AGD in men with a history of TC and controls, and furthermore to examine AGD during testosterone replacement therapy in adulthood. Study participants were TC survivors with a mild Leydig cell insufficiency who participated in a randomized double-blind study of testosterone replacement therapy versus placebo for 52 weeks (N = 69). Men from the general population were prospectively included from a study on testicular function as controls (N = 67).
PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured two variants of AGD; as our primary outcome the anoscrotal distance (AGDas) measured from the centre of the anus to the posterior base of the scrotum, and secondarily the anopenile distance (AGDap) measured from the anus to the cephalad insertion of the penis. Using multiple regression analysis, the mean difference in AGD between TC survivors and men from the general population was assessed, adjusted for height, BMI and examiner. Next, AGD was measured before and after 52 weeks of treatment with testosterone or placebo, and with covariance analysis differences between the two groups at follow-up was assessed after adjustment for baseline AGD, examiner, BMI and change in BMI during treatment.
TC survivors had a shorter AGDas (-0.84 cm, 95% CI: -1.31; -0.37) compared to men from the general population, and AGDas did not differ between the testosterone and placebo treated group at follow-up (0.11 cm, 95% CI: -0.22; 0.44). In contrast, AGDap was not shorter in TC survivors after adjustment (0.05 cm, 95% CI: -0.30; 0.39), and was 0.48 cm longer (95% CI: 0.13; 0.82) at follow-up in the testosterone treated compared to the placebo-treated group.
LIMITATIONS, REASONS FOR CAUTION: A limitation of the study is that the number of included men was limited, and results need confirmation in a larger study. Furthermore, TC survivors were significantly older than controls. For the comparison of AGD in TC survivors and controls, it was not possible to conduct the examinations with the examiner being blinded to which group he was examining, and it cannot be excluded that this can cause a bias.
The shorter AGDas in TC survivors compared to controls, which did not change upon adult testosterone replacement therapy, supports the hypothesis that reduced AGD is part of the testicular dysgenesis syndrome and may be a marker of disrupted foetal testicular development. By contrast, AGDap was not shorter in TC survivors and might be modestly sensitive to adult testosterone treatment, and thus inferior to AGDas as a constant postnatal marker of the foetal androgen environment.
STUDY FUNDING/COMPETING INTEREST(S): Expenses were paid by the Department of Oncology, Copenhagen University Hospital, Rigshospitalet. Kiowa Kirin International covered expenses for Tostran and placebo. The Danish Cancer Society, The Danish Cancer Research Foundation, the Preben & Anna Simonsen Foundation, and Rigshospitalet have supported the study. L.P. was financed by the Research Fund of the Capital Region of Denmark. The authors have no competing interests.
Part of the study is based on men participating in a randomized controlled trial registered at ClinicalTrials.gov, NCT02991209, 25 November 2016.
睾丸癌（TC）幸存者的肛殖距（AGD）是否短于一般人群中的男性，并且 AGD 是否会受到成年后睾丸激素替代疗法的影响？
AGD，即从肛门到阴囊的距离（AGDas），在 TC 幸存者中较短，并且不会因睾丸激素替代疗法而改变。
动物研究表明，AGD 是胎儿雄激素作用的产后“读出”，并且认为雄性后代的 AGD 较短是由于生殖系统在子宫内受到干扰而导致的女性化的标志。同样，在人类研究中测量 AGD 表明 AGD 是睾丸发育不良综合征假说的一部分，该假说提出，男性生殖障碍，如尿道下裂、隐睾、某些精液质量受损和 TC，都具有共同的胎儿起源。
研究设计、大小和持续时间：本研究旨在评估 TC 幸存者和对照组男性的 AGD，并进一步研究成年后睾丸激素替代治疗期间的 AGD。研究参与者是轻度莱迪希细胞功能不全的 TC 幸存者，他们参加了一项随机双盲研究，比较睾丸激素替代治疗与安慰剂治疗 52 周（N=69）。男性来自一般人群，前瞻性地从睾丸功能研究中作为对照组纳入（N=67）。
参与者/材料、设置和方法：我们测量了两种 AGD 变体；作为我们的主要结果，从肛门中心到阴囊后基底部测量的肛殖距（AGDas），其次是从肛门到阴茎头插入处测量的肛阴茎距（AGDap）。使用多元回归分析，评估 TC 幸存者和一般人群男性之间的 AGD 平均值差异，调整了身高、BMI 和检查者。接下来，在接受睾丸激素或安慰剂治疗 52 周前后测量 AGD，并在调整基线 AGD、检查者、BMI 和治疗期间 BMI 变化后，使用协方差分析评估随访时两组之间的差异。
TC 幸存者的 AGDas 比一般人群男性短（-0.84cm，95%CI：-1.31；-0.37），并且在随访时睾丸激素和安慰剂治疗组之间的 AGDas 没有差异（0.11cm，95%CI：-0.22；0.44）。相比之下，调整后 AGDap 在 TC 幸存者中并不短（0.05cm，95%CI：-0.30；0.39），并且在接受睾丸激素治疗的组中比接受安慰剂治疗的组长 0.48cm（95%CI：0.13；0.82）。
局限性、谨慎的原因：本研究的一个局限性是纳入的男性人数有限，需要在更大的研究中确认结果。此外，TC 幸存者明显比对照组年长。对于 TC 幸存者和对照组的 AGD 比较，由于无法对检查者进行盲法检查，因此无法进行检查，不能排除这可能会导致偏差。
TC 幸存者的 AGDas 与对照组相比较短，而在成年睾丸激素替代治疗后没有改变，支持了减少的 AGD 是睾丸发育不良综合征的一部分的假设，并且可能是胎儿睾丸发育受损的标志。相比之下，TC 幸存者的 AGDap 不短，并且可能对成年睾丸激素治疗适度敏感，因此作为胎儿雄激素环境的产后恒定标志物不如 AGDas。
研究资金/利益冲突：丹麦癌症协会、丹麦癌症研究基金会、Preben & Anna Simonsen 基金会和 Rigshospitalet 为该研究提供了支持。作者没有竞争利益。丹麦首都大区研究基金资助 L.P.。费用由哥本哈根大学医院肿瘤学系支付。Kiowa Kirin International 支付了 Tostran 和安慰剂的费用。该研究的一部分基于参加随机对照试验的男性，该试验在 ClinicalTrials.gov 上注册，NCT02991209，2016 年 11 月 25 日。
