Baskin L S, Sutherland R S, DiSandro M J, Hayward S W, Lipschutz J, Cunha G R
Department of Urology, University of California San Francisco Children's Medical Center, USA.
J Urol. 1997 Sep;158(3 Pt 2):1113-8. doi: 10.1097/00005392-199709000-00108.
Recent rat studies suggest that early exposure to exogenous testosterone accelerates the loss of androgen receptors and compromises eventual penile length. In humans we hypothesize that down regulation of the androgen receptor is not the mechanism that stops penile growth. To test this hypothesis we investigated the effects of androgen deprivation and supplementation on the developing human penis.
A total of 15 normal human fetal penises at 7 to 19 weeks of gestation (mean plus or minus standard deviation 12 +/- 4.5) was divided in half sagittally. Specimens were grafted beneath the renal capsule of male athymic nude mice or nude rats. Three groups of host animals were prepared, including 10 with no testosterone that were castrated at grafting, 15 with testosterone and 5 with super testosterone in which 50 mg. testosterone propionate pellets were implanted subcutaneously at grafting. Each fetal penile specimen was its own control, since half was implanted into an intact animal and the other into a castrated or super testosterone host. Six weeks after grafting the specimens were analyzed for gross size (length), histology and expression of androgen receptors.
All human fetal penile specimens grew from the nadir size and appeared as white exophytic growths on the surface of the host kidneys. Normal grafts were larger than castrate specimens (mean 6.9 +/- 2.1 versus 3.9 +/- 2.1 mm., p = 0.014). Mean length of the super testosterone specimens (7.3 +/- 2.3 mm.) was not significantly greater than that of normal specimens (p = 0.797). Histological analysis revealed that all specimens were composed of viable penile tissue. Cellular density of the castrate penises was approximately 2 times greater than that of the normal and super testosterone specimens (40.6 +/- 5.9 versus 25.1 +/- 2.8 cells per cm.2, p > 0.001), as calculated on enlarged micrographs. Supraphysiological doses of testosterone did not change the histology compared to controls. Immunohistochemical localization revealed androgen receptors expressed throughout the corporeal bodies, surrounding stroma and penile skin with intracellular localization to nucleus. The mean proportion of cells expressing androgen receptors was higher in the castrate (29.4 +/- 5.2 cells per cm.2) than in the normal (24.0 +/- 3.7) and super testosterone (24.7 +/- 4.5) grafts (p = 0.005). However, in regard to growth there was no change in the proportion of androgen receptor positive cells among the groups.
Testosterone influences penile growth, possibly as a result of extracellular stromal expansion. The number of androgen receptor positive cells in the human fetal penis did not change among the castrate, normal and super testosterone hosts. These experiments support the hypothesis that penile growth cessation is mediated by mechanisms other than down regulation of the androgen receptor. Furthermore, these data support the hypothesis that early administration of androgen to prepubertal male individuals does not result in a shorter phallus in adulthood.
近期的大鼠研究表明，早期暴露于外源性睾酮会加速雄激素受体的丧失，并影响最终的阴茎长度。我们推测在人类中，雄激素受体的下调并非阴茎生长停止的机制。为验证这一假设，我们研究了雄激素剥夺和补充对发育中的人类阴茎的影响。
选取15个妊娠7至19周的正常人类胎儿阴茎（平均±标准差为12±4.5周），沿矢状面将其分成两半。将标本移植到雄性无胸腺裸鼠或裸大鼠的肾包膜下。制备三组宿主动物，包括10只在移植时去势且未给予睾酮的动物、15只给予睾酮的动物以及5只给予超量睾酮的动物，后者在移植时皮下植入50mg丙酸睾酮丸剂。每个胎儿阴茎标本自身作为对照，因为一半植入完整动物体内，另一半植入去势或给予超量睾酮的宿主动物体内。移植6周后，对标本的总体大小（长度）、组织学和雄激素受体表达进行分析。
所有人类胎儿阴茎标本均从最低尺寸开始生长，在宿主肾脏表面呈现为白色外生性生长物。正常移植标本大于去势标本（平均6.9±2.1对3.9±2.1mm，p = 0.014）。超量睾酮标本的平均长度（7.3±2.3mm）与正常标本相比无显著差异（p = 0.797）。组织学分析显示，所有标本均由有活力的阴茎组织构成。根据放大的显微照片计算，去势阴茎的细胞密度约为正常和超量睾酮标本的2倍（每平方厘米40.6±5.9对25.1±2.8个细胞，p>0.001）。与对照组相比，超生理剂量的睾酮并未改变组织学。免疫组化定位显示，雄激素受体在整个海绵体、周围基质和阴茎皮肤中均有表达，且在细胞内定位于细胞核。去势组中表达雄激素受体的细胞平均比例（每平方厘米29.4±5.2个细胞）高于正常组（24.0±3.7个细胞）和超量睾酮组（24.7±4.5个细胞）（p = 0.005）。然而，就生长而言，各组间雄激素受体阳性细胞的比例并无变化。
睾酮可能通过细胞外基质扩张影响阴茎生长。在去势、正常和超量睾酮宿主的人类胎儿阴茎中，雄激素受体阳性细胞的数量并未改变。这些实验支持了阴茎生长停止是由雄激素受体下调以外的机制介导的这一假设。此外，这些数据支持了青春期前男性个体早期给予雄激素不会导致成年后阴茎较短的假设。
