The objective was to verify the hypothesis of a 'first uterine pass effect' or direct preferential vagina-to-uterus transport, suggested by the evidence of higher than expected uterine tissue concentrations after vaginal administration of progesterone; we used a human ex-vivo uterine perfusion model. A mixture of tritiated (3H) and unlabelled progesterone was applied to the cuff of vaginal tissue remaining attached to the cervix after hysterectomy. At the end of the perfusion period (up to 12 h), 3H and 14C radioactivity was measured in samples of uterine tissue. Tritiated water and [14C]dextran were tested to determine the extent of non-specific vagina-to-uterus transport (leaks). Finally, sections of uterine tissue exposed only to [3H]progesterone were prepared for autoradiography. By 4-5 h after application progesterone had diffused to the entire uterus and had reached a steady state; 4 h after application, progesterone concentrations reached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrial tissue respectively. Endometrial extraction of progesterone was higher when the experiment was performed on uteri obtained during the luteal phase (280 +/- 156 ng/100 mg of endometrial tissue) than those removed during the proliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg of endometrial tissue). These data demonstrate that a 'first uterine pass effect' occurs when drugs are delivered vaginally, thereby providing an explanation for the unexpectedly high uterine concentrations relative to the low serum concentration observed after vaginal administration. Hence, the vaginal route permits targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.
The epidemiology, aetiology, diagnosis and clinical management of spontaneous and recurrent abortion and of the failure of embryo implantation are discussed in a retrospective overview of the major studies conducted since 1975 identified through a Medline search. Infertile women who experienced spontaneous single (32%) and recurrent (0.5%) abortion as well as those who became pregnant after induction of ovulation with gonadotrophins (abortion rate 17-31%) and those who underwent assisted fertilization programmes (abortion rate 18-34%) are considered. Causes and treatments are here reported. Medical treatments for immunologically mediated abortion (IMA) are based on prednisolone, heparin, aspirin and intravenous immunoglobulin. Efficacy of the medical treatment of patients with a history of IMA has yet to be completely demonstrated. Genetic disorders are possible causes of both failure in implantation and early abortion; this cause is more prominent with advanced age and currently cannot be treated. Endocrine factors may also be responsible for miscarriage, and correction of hormone abnormalities is discussed. Infections, endometriosis and psychological factors are other possible important causes of embryo loss without specific widely accepted treatments. Prominent areas of research are the identification of genetic preimplantation abnormalities, and pharmacological intervention for abnormal spontaneous uterine contractility. The data here reported are encouraging, but the efficacy of different treatments is still not convincing. The information available is sufficient to develop new diagnostic and therapeutic tools to evaluate their efficacy in reducing spontaneous abortion at an early stage.
Background: To evaluate the improvement of the term delivery rate after uterine surgery in various uterine malformations. Methods: 170 patients were eligible for the present retrospective case series study. Data were weighted for the number of pregnancies observed (n = 218) after surgical intervention, stratified to the number of previous abortions (at least 2) and type of malformation. Results: Before surgery, the overall term delivery rate was 5.5%. After surgery, the overall term delivery rate was 59% (absolute benefit increase, ABI, was 54.5) and correlated with the number of previous abortions (69.7% ABI = 64.2, 56.5% ABI = 51 and 26.3% ABI = 20.8 for 2, 3–4 and >4 abortions, respectively; p = 0.0008, log-rank test). Data stratified according to uterine malformations yielded the following term delivery rate: 66.7% for T-shaped uterus, 62.8% for septum/partial septum and 55.6% for arcuate uterus (NS, log-rank test). The number of previous abortions and maternal age also affected the term delivery rate. Their effect upon the term delivery rate, expressed as an odds ratio, was 1.73 (95% CI: 1.20–2.49) and 1.11 (95% CI: 1.05–1.18), respectively. Conclusion: The term delivery rate was about 10-fold higher after surgery. T-shaped uterus surgery yielded the best term delivery rate.
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