Effect of tamoxifen alone and in combination with RU 486 on the endometrium in the mid-luteal phase

The effects of RU 486 combined with tamoxifen and tamoxifen alone on hormonal parameters and endometrial development at the time of implantation were studied. Measurements of cytosolic oestrogen and progesterone receptors in endometrium and placental protein 14 (PP14) in plasma were also included. Three dosage schedules were used: single oral dose of 40 mg tamoxifen alone and in combination with 200 mg RU 486, and 40 mg tamoxifen for three consecutive days starting on the first day after the luteinizing hormone (LH) surge. The combined treatment prolonged the luteal phase (P < 0.05) and increased the plasma levels of progesterone. A single dose of tamoxifen did not affect the bleeding pattern and plasma hormone levels, but raised plasma oestradiol and LH with the 3-day treatment. The endometrium was retarded after the combined and the 3-day treatment with tamoxifen. Concentrations of cytosolic progesterone receptors were higher after the combined therapy, but were unaffected after tamoxifen only. PP14 levels were higher (P < 0.05) after repeated tamoxifen doses than in controls, but were lower with combined treatment. Progesterone and oestrogen are evidently necessary for endometrial maturation during the secretory phase of the menstrual cycle. PP14 levels in plasma cannot be used for clinical assessments of endometrial function because high levels coincide with disturbed endometrial developmen

The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium

Seventeen healthy women aged 24-45 years with regular menstrual periods, proven fertility and not using steroidal contraceptives or IUD were recruited for the study. The volunteers were followed during one control, one treatment and one follow-up cycle. Daily morning urine samples were obtained during the control and the treatment cycle. The samples were analysed with regard to pregnanediol glucuronide (P2-G), oestrone glucuronide (E1-G), oestradiol (E2), progesterone (P4), LH and creatinine. During the entire 3-month study the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU486 daily either on cycle days 7-10 (n = 7) or on cycle days 20-23 (n = 10). An endometrial biopsy was taken on cycle day 10 in the first group and on cycle days 21-28 in the second group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle length due to a delay of the oestrogen and LH surge. However, once the oestrogen concentration started to increase, the remaining part of the cycle was normal. The length of the follow-up cycle was similar to that of the control cycle. The morphology of the endometrium did not differ from control samples taken from untreated women at the same time of the cycle. All ovulating women (n = 9) treated in the mid-luteal phase started to bleed on the 3rd to 4th day of the treatment. In four of these women the bleeding was scanty and followed by a menstrual-like bleeding at expected time, while in the remaining five volunteers the treatment bleeding was heavier and not followed by a new bleeding until a month later. The duration of the secretory phase was 16.5 ± 1.3 days in women with two bleeding episodes and 11.8 ± 1.9 days in women with one bleeding episode (P < 0.05). The hormonal parameters were similar in both groups up to the start of the treatment. In the patients with one bleeding episode, the treatment was associated with a reduction in progesterone concentration, while in the patients with two bleeding episodes the progesterone concentration remained elevated until the second bleeding episode. Light microscopic examination of the endometrium revealed unique changes in the endometrial morphology. The results indicate that RU486 acts mainly on the endometrium but a direct or indirect effect on the corpus luteum cannot be excluded. The age of the corpus luteum may be of importance for its susceptibility to RU486 treatmen

Binding of Complement Factor H to Loop 5 of Porin Protein 1A: A Molecular Mechanism of Serum Resistance of Nonsialylated Neisseria gonorrhoeae

Neisseria gonorrhoeae isolated from patients with disseminated infection are often of the porin (Por1A) serotype and resist killing by nonimmune normal human serum. The molecular basis of this resistance (termed stable serum resistance) in these strains has not been fully defined but is not related to sialylation of lipooligosaccharide. Here we demonstrate that Por1A bearing gonococcal strains bind more factor H, a critical downregulator of the alternative complement pathway, than their Por1B counterparts. This results in a sevenfold reduction in C3b, which is >75% converted to iC3b. Factor H binding to isogenic gonococcal strains that differed only in their porin serotype, confirmed that Por1A was the acceptor molecule for factor H. We identified a surface exposed region on the Por1A molecule that served as the binding site for factor H. We used gonococcal strains with hybrid Por1A/B molecules that differed in their surface exposed domains to localize the factor H binding site to loop 5 of Por1A. This was confirmed by inhibition of factor H binding using synthetic peptides corresponding to the putative exposed regions of the porin loops. The addition of Por1A loop 5 peptide in a serum bactericidal assay, which inhibited binding of factor H to the bacterial surface, permitted 50% killing of an otherwise completely serum resistant gonococcal strain. Collectively, these data provide a molecular basis to explain serum resistance of Por1A strains of N. gonorrhoeae

Amelioration of sexual adverse effects in the early breast cancer patient

As the number of breast cancer survivors increases, the long term consequences of breast cancer treatment are gaining attention. Sexual dysfunction is a common complaint amongst breast cancer survivors, and there are few evidence based recommendations and even fewer well designed clinical trials to establish what treatments are safe or effective in this patient population. We conducted a PubMed search for articles published between 1995–2009 containing the terms breast cancer, sexual dysfunction, libido, vaginal dryness, testosterone, and vaginal estrogen. We initially reviewed articles focusing exclusively on sexual issues in breast cancer patients. Given the paucity of clinical trials addressing sexual issues in breast cancer patients, we also included studies evaluating both hormone and non-hormone based interventions for sexual dysfunction in post-menopausal women in general. Among breast cancer survivors, vaginal dryness and loss of libido represent some of the most challenging long term side effects of breast cancer treatment. In the general post-menopausal population, topical preparations of estrogens and testosterone both appear to improve sexual function; however there are conflicting reports about the efficacy and safety of these interventions in women with a history of breast cancer, and further research is warranted

Platelets and thrombogenesis--Current concepts

Anticoagulants, although effective in the treatment of venous thrombotic disease, have not been generally helpful in preventing arterial thrombosis. The reason for this disparity may lie in the type of clot formed in each case. In veins a "red thrombus" is formed, consisting of erythrocytes, leukocytes, fibrin, and platelets randomly distributed, whereas in arteries a "white thrombus" consisting mainly of platelets and fibrin strands is the obstructing lesion1. The predominance of platelets in this "white" clot has focused attention on their importance in arterial occlusion and has suggested that therapeutic maneuvers directed at platelet function may be more useful than standard anticoagulant therapy. This review presents the recent advances in the study of platelet morphology and function, and concludes by discussing possible therapeutic avenues.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34128/1/0000412.pd