Modulation of Melatonin Receptors Regulates Reproductive Physiology: The Impact of Agomelatine on the Estrus Cycle, Gestation, Offspring, and Uterine Contractions in Rats.

Agomelatine is a pharmaceutical compound that functions as an agonist for melatonin receptors, with a particular affinity for the MT1 and MT2 receptor subtypes. Its mode of action is integral to the regulation of diverse physiological processes, encompassing the orchestration of circadian rhythms, sleep-wake cycles, and mood modulation. In the present study, we delve into the intricate interplay between agomelatine and the modulation of estrus cycles, gestation periods, offspring numbers, and uterine contractions, shedding light on their collective impact on reproductive physiology. Both in vivo and in vitro experiments were performed. Wistar Albino rats, divided into four groups: two non-pregnant groups (D1 and D2) and two pregnant groups (G1 and G2). The D1 and G1 groups served as control groups, while the D2 and G2 groups received chronic agomelatine administration (10 mg/kg). Uterine contractions were assessed in vitro using myometrial strips. Luzindole, a melatonin receptor antagonist, was employed to investigate the pathway mediating agomelatine's effects on uterine contractions. In in vivo studies, chronic agomelatine administration extended the diestrus phase (p<0.05) in non-pregnant rats, prolonged the gestational period (p<0.01), and increased the fetal count (p<0.01) in pregnant rats. Additionally, agomelatine reduced plasma oxytocin and prostoglandin-E levels (p<0.01) during pregnancy. In vitro experiments showed that agomelatine dose-dependently inhibited spontaneous and oxytocin-induced myometrial contractions. Luzindole (2 µM) reverse the agomelatine-induced inhibition of myometrial contractions. These findings suggest that agomelatine holds the potential to modulate diverse reproductive parameters during the gestational period, influencing estrus cycling, gestational progression, offspring development, and the orchestration of uterine contractions.

Efficacy of gemcitabine in heavily pretreated advanced ovarian cancer patients.

Single agent gemcitabine was used in recurrent epithelial ovarian cancer patients after standard treatment with debulking surgery and platin-paclitaxel based chemotherapy. Response rates and toxicity results were evaluated retrospectively. Gemcitabine was given in 1000 mg/m2 intravenous infusion over 30 minutes at 1, 8, 15 days of every 28 days. Clinical response was evaluated with clinical findings, serum CA 125 levels, and computerized tomography. Twenty-two patients--ten as second-line, 11 as third-line, and one as fourth line--received gemcitabine. Seven patients received six courses, nine cases three, five cases two and one case one course of treatment. There were four (18.2%) partial and two (9.1%) complete responses with an overall response rate of 27.3%. Stable disease was also observed in three more cases. The progression-free interval was found to be a median of three months. Grade 3-4 neutropenia was seen in two (9.1%) and grade 3-4 thrombocytopenia was seen in four (18.2%) cases. Pancytopenia was observed in one (4.5%) patient. There was no grade 3-4 non-hematological toxicity. Antitumoral activity is encouraging in heavily pretreated ovarian cancer patients. A short progression-free interval is noticeable in responding cases. Toxicity is mainly hematologic and moderate.

Telomere-specific fluorescence in situ hybridization analysis of couples with five or more recurrent miscarriages.

Fluorescence in situ hybridization analysis using telomere specific probes has been used to detect cryptic translocations in the chromosomal telomeric regions. This study was performed in five clinically normal couples who have had five or more spontaneous abortions and whose karyotypes were found to be normal using conventional cytogenetic techniques. Using the telomere specific probes, in one couple we determined a cryptic translocation between chromosome 3 and 10, and, in another couple, the signal in chromosome 20 was detected in another chromosome, which was probably a D group chromosome. Additionally, in the latter and also in two other couples, we observed a polymorphism. The approach will be helpful for screening cryptic translocations using telomere specific multiple probe sets in couples with recurrent miscarriages. As prenatal diagnosis will be available for these couples for future pregnancies, it will be possible to help these families to have healthy fetuses.

Benign persistent papular acantholytic and dyskeratotic eruption of the vulva: a case report.

We report a case of 44-year-old woman with persistent pruritic papules on the left and right labium majus of the vulva. Histopathologic examination of the vulvar biopsy specimen revealed a suprabasal separation of the epidermis with acantholysis and dyskeratosis.

Immunohistochemical staining properties of PCNA, Ki-67, p53, beta-hCG and HPL in trophoblastic disease.

OBJECTIVE: In this study proliferating markers PCNA (proliferating cell nuclear antigen) Ki-67 and mutation of supressor gene p53 were investigated in gestational trophoblastic disease (GTL). These markers were tested by using immunostaining with beta subunits of human chorionic gonadotropin (hCG) and human placental lactogen (HPL). MATERIAL AND METHODS: Twenty curetting samples, 20 spontaneous abortions, 16 hydatidiform moles and two choriocarcinomas were studied and compared. Hydatidiform moles were subdivided into 10 complete and six partial moles by using flow cytometry analysis. All slides were stained with PCNA, Ki-67, p53, hCG, and HPL immunohistochemically. PCNA and Ki-67 stained slides were studied quantitatively to determine the PCNA and Ki-67 index. Other slides that were stained with p53, hCG, HPL were evaluated according to staining percentage and intensity. Staining properties of all groups were compared with each other. Variance analysis and the Mann Whitney U test were used for statistical analysis. Choriocarcinomas were not included in the statistical analysis. Ki-67 and the PCNA index in two choriocarcinoma cases found 81.4% and 41%, and 44% and 64%, respectively. One case was stained in 70% with (++) intensity by p53. While both were stained in 80% with (++) intensity by hCG, one was stained in 30% field (+) intensity by HPL. RESULTS: The four groups of complete and incomplete diagnosed hydatiform moles, spontaneous abortions and retention curettage were matched in pairs and evaluated according to the PCNA index. This index showed significant differences among the groups. The differences among the Ki-67 index, p53, hCG and HPL staining properties were not statistically significant. CONCLUSION: Our findings showed that PCNA is a significant and useful marker for trophoblastic diseases and can be used as a prognostic factor.

Toxicity of chemotherapeutical protocols in the treatment of uterine sarcomas (Vincristine, actinomycin D, Cyclophosphamide VAC versus ifosfamide).

OBJECTIVE: Uterine sarcomas are rare tumors which account for 1% of all genital tract malignancies. They have a poor prognosis with an overall survival of under 50% at 2 years. The benefit of chemotherapy is unclear and different chemotherapy protocols are used for the treatment of uterine sarcomas. But there is little experience about their toxicity because of the limited case series. So we compared VAC protocol and ifosfamiide for toxic effects. MATERIAL AND METHOD: We reviewed 13 cases which were diagnosed as uterine sarcomas and treated with surgery plus chemotherapy at The Department of Obstetrics and Gynecology, Akdeniz University School of Medicine from 1990 to 1995. Data were obtained from patient files. RESULTS: Mean age was 55.7 (range 38-70), 7 (53.8%) patients had malignant mixed mullerian tumors and 6 (46.1) had leiomyosarcomas. A total of 32 courses of chemotherapy were given -20 ifosfamide and 12 VAC therapy. Leucopenia, hepatic dysfunction and peripheral neuropathy were more frequent in the VAC group as 75%, 16.6%, versus 30%, 0%, 0%, in the iFosfamide group respectively. However, urothelial toxicity (35%) was more common in the ifosfamide group. CONCLUSION: VAC protocol is more toxic for the liver, hematopoietic and peripheral neurologic system. On the other hand the major toxicity of ifosfamide was on the urinary tract. Ifosfamide may be a good choice with less toxicity than VAC therapy in the treatment of uterine sarcomas.

Postmenopausal vulvar pruritus--colposcopic diagnosis and treatment.

Vulvar pruritus is a common symptom in post-menopausal women and treatment is easy if the diagnosis is duly recognized. The purpose of this study is to show the importance of colposcopic examination and directed biopsies in 27 post-menopausal women with pruritus. Biopsy sites were selected by colposcopy. The prevalence of vulvar pruritus, vulvar pathologies, vulvar dystrophies and vulvar intraepithelial lesions (VIN) were 2.18%, 1.49%, 0.94% and 0.07% respectively. Vulvar dystrophies were treated by topical steroids and success rate was 100%. All patients with vulvar pruritus need examination under colposcopy to define optimal therapy and to exclude atypia or malignancy.

Urinary calcium to creatinine ratio for predicting preeclampsia.

Urinary calcium excretion decreases in preeclampsia. To determine the predictability of preeclampsia with hypocalciuria, we investigated the calcium to creatinine ratio and the calcium level of a spot urine sample in 56 primigravid patients aged less than 25 years. Of these 56 cases, 44 remained normotensive and preeclampsia developed in eight cases. There were four cases of gestational hypertension and they are not included in the statistical analysis. The mean age, the mean gestational age at entrance into the study, the mean urine calcium concentration, the mean birthweight, and the mean gestational age at delivery were similar between the normotensive and preeclamptic groups. The mean calcium to creatinine ratio is found to be significantly lower in the preeclamptic group (0.0475 +/- 0.0260) compared with the normotensive group (0.1466 +/- 0.1353; p < 0.0001). A cutoff level of 0.066 for the calcium to creatinine ratio with the use of a receiver operator curve yielded a sensitivity of 75%, a specificity of 86%, and a positive and negative predictive value of 55% and 95%, respectively. The results of this study suggest that a single urine calcium to creatinine ratio might be an effective marker for predicting preeclampsia in a high-risk population.

Polycystic ovaries in association with müllerian anomalies.

The polycystic ovary syndrome, whose etiopathogenesis is not clearly understood, has a wide spectrum of clinical presentations, and may co-exist with other pathologic conditions. In this study, we evaluated the prevalence of ultrasound-defined polycystic ovaries (PCO) in patients with müllerian anomalies (n = 167), and those without müllerian anomalies (n = 3165) from 1990 to 1994, in a population markedly composed of infertility patients. PCO were found in 50 (29.9%) patients in the study group, compared to 637 (20.1%) patients in controls (P < 0.01). Müllerian anomalies were further grouped according to the American Fertility Society (AFS) classification and it was found that patients with the septate uteri and bicornuate uteri malformations had a higher prevalence of PCO than the controls (P < 0.001, P < 0.05, respectively). Although a difference existed in the percentage of PCO in patients with unicornuate uteri and didelphic uteri compared to controls, this difference did not reach statistical significance (P > 0.05). We conclude that, as PCO are more prevalent in certain müllerian anomalies, an embryogenetic defect may also be involved in the etiopathogenesis of PCO.

The hormonal profile in ectopic pregnancies.

We prospectively investigated the maternal serum level of beta- human chorionic gonadotropin (beta-hCG) progesterone (P), estradiol (E2), human placental lactogen (HPL), alfa-fetoprotein (AFP) and cancer antigen 125 (CA 125) during the first trimester of normal and abnormal pregnancies. Serum samples were obtained from 20 women with normal intra-uterine pregnancy (IUPs). Fifteen whose pregnancies were complicated with spontaneous abortion and 31 with surgically and pathologically confirmed ectopic pregnancies (EPs). The mean serum levels of beta-hCG, E2 and P in patients with Eps (9490.55 +/- 3071.2 mIU/ml, 100.1 +/- 22.09 pg/ml, 4.18 +/- 1.19 ng/ml, respectively) were significantly lower than those measured in normal IUPs (73796.8 +/- 15554.7 mIU/ml, 500.15 +/- 98.84 pg/ml, 19.2 +/- 2.8 ng/ml respectively (p < 0.001) and significantly lower than in patients with spontaneous abortion (22524 +/- 6213 mIU/ml, p < 0.05, 339.8 +/- 112.16 pg/ml, p < 0.01, 10.59 +/- 3.03 ng/ml, p < 0.05 respectively). No significant difference was recorded with respect to serum levels of HPL, AFP and CA 125 among the groups. We also investigated the diagnostic value of simple E2 and P in patients with EPs. We could not identify a discriminatory cutoff value because there was a considerable overlap in serum P ans E2 levels between the patients with IUPs and EPs. In conclusion, it is not possible to define a cutoff discriminatory value of P and E2 that completely separates ectopic from IUPs, but the addition of these assays to the workup of a patient with suspected EP may facilitate the earlier diagnosis of EP.

The hormonal profile in ectopic pregnancies.

The hormonal profile in a patient with an ectopic pregnancy (EP) differs in many respects from that of a patient with a normal intrauterine pregnancy (IUP). Although there are several reports using different hormones for early diagnosis of ectopic pregnancy most of the results are contradictory. In this study, therefore, we prospectively investigated the maternal serum level of beta-human chorionic gonadotropin (beta-hCG), progesterone (P), estradiol (E2), human placental lactogen (HPL), alfafetoprotein (AFP) and cancer antigen 125 (CA 125) during the first trimester of normal and abnormal pregnancies. Serum samples were obtained from 20 women with normal IUPs, 15 women whose pregnancies complicated with spontaneous abortion and 31 women with surgically and pathologically confirmed EPs. The mean serum levels of beta-hCG, E2 and p in patients with EPs (9490.55 +/- 3071.2 mlU/ml, 100.1 +/- 22.09 pg/ml, 4.18 +/- 1.19 ng/ml, respectively) were significantly lower than those measured in normal IUPs (73796.8 +/- 15554.7 mlU/ml, 500.15 +/- 98.84 pg/ml, 19.2 +/- 2.8 ng/ml, respectively p < 0.001) and significantly lower than in patients with spontaneous abortion (22524 +/- 6213 mlU/ml, p < 0.05, 339.8 +/- 112.16 pg/ml, p < 0.01, 10.59 +/- 3.03 ng/ml, p < 0.05 respectively). No significant difference was recorded with respect to serum levels of HPL, AFP and CA 125 among the groups. We also investigated the diagnostic value of simple E2 and P in patients with EPs. We could not identify a discriminatory cutoff value because there was a considerable overlap in serum P and E2 levels between the patients with IUPs and EPs.(ABSTRACT TRUNCATED AT 250 WORDS)