Effects of long-term treatment with resveratrol and subcutaneous and oral estradiol administration on the pituitary-thyroid-axis.

The lack of estrogen during menopause is associated with various symptoms including osteoporosis, cardiovascular diseases, and menopausal symptoms. For many years, conventional hormone replacement therapy has been successfully used to treat these conditions. However, in light of recent studies that draw attention to potential hazards of conventional HRT, various attempts were undertaken to search for alternatives of classical HRT. Phytoestrogens are supposed to ameliorate various discomforts associated with menopause. Resveratrol (RES) is present in red wine, grapes and peanuts and has been implicated in cardioprotection and prevention of adverse side effects observed after regular HRT. As the pituitary-thyroid axis is a target of estrogen action, we first assessed the effects of E2 administration on thyroid hormone stimulating hormone releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion from pituitary cell cultures in vitro. Our data reveal that E2 treatment augments the TRH-induced TSH secretion. We furthermore designed a long-term study of three months to assess the effects of subcutaneous and oral administration of 17beta-estradiol (E2), as well as the actions of RES on the pituitary-thyroid axis in ovariectomized (OVX) female rats. Our results demonstrate that serum levels of 1.0 and 8.1 microM RES lead to a significant increase in total serum triiodthyronine (T3) levels. OVX induces TSHbeta mRNA in the adenohypohysis and E2 treatment attenuates this effect. Treatment of rats with subcutaneous implants of E2 does not affect the pituitary-thyroid axis, whereas orally applied E2 benzoate (E2B) increases plasma TSH and total thyroxine (T4) in OVX rats. In all animals, we could not detect changes in thyroid morphology as assessed by hematoxylin-eosin (HE) and Perjod-Acid Schiff's (PAS) staining.     

Incidence of asthma and net change in symptoms in relation to changes in obesity.

The incidence of asthma has been reported to be associated with obesity. An alternative analysis, of net change in prevalence, does not require exclusion of those with asthma at baseline. Follow-up data were obtained from 9,552 participants in the European Community Respiratory Health Survey and the Swiss cohort Study on Air Pollution and Lung Disease in Adults. Incidence of asthma was analysed by proportional hazards regression, and net changes in symptoms and asthma status by generalised estimating equations, by obesity group. Incidence and net change in ever having had asthma were greater in females than in males, and in participants who remained obese compared with those who were never obese (hazard ratio 2.00, 95% confidence interval 1.25-3.20; excess net change 2.8%, 0.4-5.3% per 10 yrs). The effect of being obese on net change in diagnosed asthma was greater in females than in males, but for net change in wheeze without a cold it was greater in males. The present results are consistent with asthma being more frequently diagnosed in females, especially obese females. These findings may help to explain the reports of a stronger association between asthma and obesity in females than in males.     

Treatment of premature ejaculation: New drugs and treatment strategies

This review discusses treatment options for men with premature ejaculation (PE), a common sexual dysfunction characterized by short ejaculatory latency, decreased sexual satisfaction, and distress. For a number of reasons, including embarrassment and the belief that PE is a normal part of aging, that it has no effective treatment, or that it will resolve itself, few men with PE seek treatment. Although several treatment options exist (eg, behavioral, cognitive, and sex therapy methods; desensitizing drugs; off-label use of antidepressants, phosphodiesterase type 5 inhibitors, or à-blockers), the majority of men with PE are not satisfied with their results. New pharmacologic drugs develped specifically for the treatment of PE are undergoing evaluation in clinical trials. For example, recent clinical research studies have revealed on-demand administration of one such drug, dapoxetine, which achieved significant improvements in ejaculatory latency, control over ejaculation, and satisfaction with sexual intercourse. In addition, partners of men who received dapoxetine likewise reported improved satisfaction with sexual intercourse. Future studies may reveal that integration of pharmacologic drugs with psychologic and/or behavioral therapy techniques may be the optimal approach to the management of PE. PE is a treatable condition, and new drugs in development may provide benefits over those available.     

IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.

Interferon-alpha (IFN-alpha) has proved effective in the treatment of hemangiomas, hemangioblastomas, and Kaposi's sarcoma. To investigate the ability of IFNs to inhibit angiosarcoma, we used two transformed murine endothelial cell lines that form angiosarcomas in vivo. SVR and MS1-VEGF cell lines express oncogenic H-ras or vascular endothelial growth factor (VEGF), respectively. IFN-alpha1,8, which is active against murine and human cells, inhibited SVR and MS1-VEGF proliferation in vitro by 40% at 10(3) U/mL (p = 0.028). In vivo, IFN-alpha1,8 inhibited SVR tumor volume by 71% (p = 0.047) and MS1-VEGF volume by 79% (p = 0.003). Tumor-induced angiogenesis was decreased in SVR tumors by 52% (p = 0.005) and in MS1-VEGF tumors by 58% (p = 0.001). Sera from IFN-alpha1,8-treated mice bearing either SVR or MS1-VEGF tumors demonstrated a 5-fold increase in IP-10/CXCL10 (p = 0.001), an IFN-induced antiangiogenic protein. Both recombinant IP-10 and IFN-alpha1,8 inhibited human umbilical vein endothelial cell (HUVEC) vessel formation in the fibrin gel assay, a three-dimensional culture model of angiogenesis, by 56% at 25 ng/mL and 50% at 1.2 ng/mL, respectively (p < 0.001). An IP-10 blocking antibody restored vessel formation to 80% of untreated controls (p = 0.001). Given the magnitude of the in vivo response, these data suggested that the antitumor effects of IFN-alpha1,8 were likely mediated through angiogenesis inhibition rather than solely by direct inhibition of tumor cell proliferation.     

Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl.

We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.     

Treatment of dysfunctional uterine bleeding in the perimenopause: the effects of adding combined estradiol/norethisterone acetate therapy to goserelin acetate treatment--a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To assess the effects of adding combined estradiol/norethisterone acetate therapy (CENT) to goserelin acetate treatment (GA) of dysfunctional uterine bleeding (DUB) in perimenopausal women. METHODS: In a randomized, placebo-controlled, double-blind trial followed by an open follow-up study, 31 perimenopausal women with DUB were recruited from gynecological outpatient departments of two Dutch hospitals and randomized for treatment with either GA/placebo or GA/CENT for 6 months followed by 18 months of GA/CENT for all. The main outcome measures were abdominal pain, number of bleeding days, double-layer endometrial thickness (DET), Greene climacteric score (GCS), visual analog scale for well-being, bone mineral density (BMD) and mammographic density (BI-RAD score). RESULTS: Abdominal pain, number of bleeding days and DET decreased in both groups, the between-group difference in decrease not being statistically significant. GCS initially showed significant improvement in the GA/CENT group. BMD decreased significantly in the GA/placebo group (-4.1%) compared with the GA/CENT group (-0.3%). Another 18 months of GA/CENT did not result in a lasting difference in BMD between groups. BI-RAD scores did not differ significantly between or within the two groups. CONCLUSIONS: Adding CENT to GA treatment for DUB in perimenopausal women initially prevented BMD loss and improved climacteric complaints, while having no negative impact on vaginal bleeding, abdominal pain or BI-RAD scores. However, prolonged treatment did not result in a lasting prevention of bone loss.     

Endometrial cancer patients have a significant risk of harboring isolated tumor cells in histologically negative lymph nodes

In this study, we examine the prevalence of finding isolated tumor cells (ITCs) in negative lymph nodes of endometrial cancer patients using immunohistochemistry. Seventy-six endometrial cancer patients with lymph nodes histologically negative for metastatic disease were examined. Nodal tissue sections were stained with anticytokeratin antibodies AE-1 and CAM 5.2. Nodes with single or groups of cells (two to four cells) < or =0.2 mm and showing cytokeratin reactivity were positive for ITCs. Findings were compared to features of the primary tumor and patient outcome. ITCs were present in 31 of 1712 lymph nodes. Fifteen (19.7%) patients had ITC-positive nodes. ITCs involved only pelvic nodes in nine cases, only para-aortic nodes in five cases, and pelvic and para-aortic in one case. Tumor in adnexa was the only pathologic feature associated with nodal ITCs (P= 0.0485). All 15 patients with nodal ITCs were alive at follow-up. One (6.7%) patient suffered recurrent disease but was alive at last encounter. Disease recurred in 5 (8.8%) of 57 patients without nodal ITCs. Two are alive without disease, two alive with disease, and one died from her cancer. In summary, a significant proportion of endometrial cancer patients have ITCs detected by immunohistochemistry in histologically negative regional lymph nodes.     

Cumulative probability of pregnancy following IVF with ICSI and fresh or frozen embryo transfer.

The authors studied the cumulative probability of pregnancy for up to 4 consecutive embryo transfer (ET) cycles with ICSI performed for male factor. Transfers could be either fresh or frozen. The clinical pregnancy rate (PR) for the first 4 cycles were similar [44% (61/366); 31% (44/138); 45% (14/31); 44% (4/9)]. Delivery rates were also similar. There was a lower PR on the second retrieval vs. the first retrieval (47% vs. 29%), but this may be related to most of the second retrievals occurring in the second transfer cycle (67%, 31/55); this may be explained by women who were poor responders and required another retrieval without a frozen ET. The majority of transfers in cycle 1 were fresh, whereas cycles 2-4 used primarily frozen-thawed embryos. These data should be helpful for patients requiring IVF with ICSI in deciding to continue with more IVF cycles or consider other