Prahalada S, Carroad E, Cukierski M, Hendrickx A G
Teratology. 1985 Dec;32(3):421-32. doi: 10.1002/tera.1420320312.
A single dose of MPA (Depo-Provera; Upjohn Co., Kalamazoo, Michigan) was administered intramuscularly to 12 time-mated pregnant cynomolgus monkeys on day 27 (+/- 2) of gestation at 25 mg/kg or at 100 mg/kg. Maternal blood samples were collected immediately prior to MPA injection and then at regular intervals until cesarean section at term (day 152 +/- 3). Infants in both dose groups had external genital abnormalities. Female infants in the low-dose groups had partial or complete labial fusion, prominent median raphe, and clitoral hypertrophy; at high doses (100 mg/kg), the female infants had complete labial fusion and a distinct penile urethra. MPA had an opposite effect on external genitalia of male infants. The penis was short and the scrotal swelling was absent or less conspicuous, and two males had hypospadias. The adrenal glands were significantly smaller (P less than 0.05) in infants of both sexes treated with 100 mg/kg. One of the infants treated with 25 mg/kg of MPA had a muscular ventricular septal defect. Serum concentrations of MPA were determined by radioimmunoassay in eight pregnant monkeys. In the 25 mg/kg group the patterns of MPA profiles in the serum were similar in all four animals. An initial peak occurred at 24-48 hr postinjection (2.7-9.6 ng/ml), followed by a slight decrease at 3 days postinjection (gestational day 30), and then a steady increase to maximum levels of 10-14 ng/ml occurring between gestational days 37 and 50. Serum levels gradually declined to concentrations below 5 ng/ml by midgestation in three of four monkeys. By comparison, both the patterns and magnitude of MPA concentration showed great interanimal variation in the 100 mg/kg group. MPA was present in cord blood at measurable concentrations in infants at both dose groups; the levels ranged from 0.6 to 8.3 ng/ml, corresponding to 40-72% of the maternal concentrations. These results demonstrate that a single injection of MPA during early pregnancy causes selective embryotoxicity in both male and female fetuses. Presence of high levels of MPA in maternal sera during the critical period of genital development can cause specific genital defects; however, the exact mechanism by which MPA causes these paradoxical genital abnormalities is unknown.
在妊娠第27天（±2天），给12只经定时交配的怀孕食蟹猴肌肉注射单剂量的醋酸甲羟孕酮（Depo - Provera；美国密歇根州卡拉马祖的Upjohn公司生产），剂量为25毫克/千克或100毫克/千克。在注射醋酸甲羟孕酮之前即刻采集母猴血样，然后定期采集，直至足月剖宫产（第152天±3天）。两个剂量组的婴儿均有外生殖器异常。低剂量组的雌性婴儿有部分或完全阴唇融合、明显的正中缝和阴蒂肥大；高剂量组（100毫克/千克）的雌性婴儿有完全阴唇融合和明显的阴茎样尿道。醋酸甲羟孕酮对雄性婴儿的外生殖器有相反的影响。阴茎短小，阴囊无肿胀或肿胀不明显，有两只雄性婴儿患有尿道下裂。100毫克/千克剂量组中，两性婴儿的肾上腺均明显较小（P<0.05）。接受25毫克/千克醋酸甲羟孕酮治疗的婴儿中有一例患有肌部室间隔缺损。用放射免疫分析法测定了8只怀孕猴子血清中醋酸甲羟孕酮的浓度。在25毫克/千克组中，所有4只动物血清中醋酸甲羟孕酮的浓度变化模式相似。注射后24 - 48小时出现初始峰值（2.7 - 9.6纳克/毫升），注射后3天（妊娠第30天）略有下降，然后在妊娠第37天至50天之间稳步上升至最高水平10 - 14纳克/毫升。4只猴子中有3只在妊娠中期血清水平逐渐降至5纳克/毫升以下。相比之下，100毫克/千克组中醋酸甲羟孕酮浓度的变化模式和幅度在动物个体间差异很大。两个剂量组婴儿的脐血中均可检测到醋酸甲羟孕酮；其水平范围为0.6至8.3纳克/毫升，相当于母体浓度的40 - 72%。这些结果表明，妊娠早期单次注射醋酸甲羟孕酮会对雄性和雌性胎儿均造成选择性胚胎毒性。在生殖器发育的关键时期，母体血清中高水平的醋酸甲羟孕酮会导致特定的生殖器缺陷；然而，醋酸甲羟孕酮导致这些矛盾的生殖器异常的确切机制尚不清楚。
