Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.

BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair.

BRCA1 and BRCA2 are tumor suppressor genes, familial mutations in which account for approximately 5% of breast cancer cases in the USA annually. Germ line mutations in BRCA1 that truncate or inactivate the protein lead to a cumulative risk of breast cancer, by age 70, of up to 80%, whereas the risk of ovarian cancer is 30-40%. For germ line BRCA2 mutations, the breast cancer cumulative risk approaches 50%, whereas for ovarian cancers, it is between 10 and 15%. Both BRCA1 and BRCA2 are involved in maintaining genome integrity at least in part by engaging in DNA repair, cell cycle checkpoint control and even the regulation of key mitotic or cell division steps. Unsurprisingly, the complete loss of function of either protein leads to a dramatic increase in genomic instability. How they function in maintaining genome integrity after the onset of DNA damage will be the focus of this review.

Loss of prostaglandin F2alpha, but not thromboxane, responsiveness in pregnant human myometrium during labour.

Prostaglandins (PG) E2, PGF2alpha and thromboxane (TX) mediate uterine contractility by targeting prostonoid EP, FP and TP receptors respectively. The aim of this study was to elucidate the function of these receptors in isolated human myometrium taken at term gestation prior to and following labour onset. Lower segment myometrial strips were immersed in organ baths in oxygenated Krebs' solution at 37 degrees C and connected to isometric force transducers. After equilibration, spontaneous activity and concentration responses to PGE2, PGF2alpha and U46619 (a stable TX mimetic) were measured as area under the curve and expressed as a percentage of the final contraction induced by hypotonic shock. Results were expressed as arithmetic means+/-s.e.m. and analysed using two-way ANOVA with Bonferroni's post hoc test. Myometrium excised at late gestation displayed the greatest spontaneous activity compared with the tissues taken during labour (P<0.001). Excitation evoked by PGF2alpha (P<0.01) and PGE2 at 10(-5) mol/l were attenuated after labour onset. U46619 consistently stimulated concentration-dependent contractions (P<0.001) and selective antagonists confirmed TP-mediated effects. The maintained responses to TX indicate crucial roles for TP receptors in the muscular tonus of the parturient uterus. This receptor and its secondary messenger system represent effective myometrial targets for tocolytic agents in both pregnancy and labour-associated disorders.

Hysteroscopic myomectomy.

Hysteroscopic myomectomy is a minimally invasive technique that eliminates the need for a laparotomy and is associated with lower morbidity than abdominal myomectomy. Its beneficial effects are reflected by the improvement in menstrual pattern, fertility rate, and overall patient satisfaction. It is usually performed as outpatient surgery but occasionally requires an overnight stay. Most patients return to full activity within 48 hours. To exploit the full potentials of this procedure, appropriate case selection and surgical expertise are essential. It should be considered as first-line conservative surgical therapy for the management of symptomatic intracavitary fibroids.