Progestogens and immunology.

Fifty percent of fetal antigens are of paternal origin. These are recognized by the maternal immune system, thereby resulting in lymphocyte activation and the induction of progesterone receptors (PRs) in immune cells. Upon binding of progesterone to PRs on lymphocytes, a downstream mediator called progesterone-induced blocking factor (PIBF) is produced. The full-length PIBF is a 90 kDa protein; however, because of alternative splicing, several smaller isoforms are also produced. While the 90 kDa molecule plays a role in cell cycle regulation, the small isoforms are localized in the cytoplasm, and after secretion, they bind to their receptors on other cells and act in a cytokine-like manner. The communication between the embryo and the maternal immune system is established through PIBF-containing extracellular vesicles. PIBF induces an increased production of Th2 cytokines and inhibits degranulation of NK cells, and by regulating the maternal immune response, it contributes to successful implantation and maintenance of pregnancy.

Operation, hormone therapy and recovery of the patients with severe forms of adenomyosis.

Endometriosis is among the prevalent gynecological diseases and diagnosed in 10% of women of reproductive age. Endometriosis/adenomyosis is becoming increasingly a health-social problem, which is associated with severe clinical manifestations and recurrent disease which has a negative effect on quality of life, women ability to work and her reproductive function. This article presents modern approaches of drug therapy to treat severe forms of adenomyosis. We have reviewed recent major studies in the field of surgical treatment of this disease, analyzed the main stages of disease progress and the results of our surgeries. Here, we are presenting our own results of long-term post-operative hormonal therapy and complex medical treatment.

A pilot study to determine whether progestogen supplementation using dydrogesterone during the first trimester will reduce the incidence of gestational hypertension in primigravidae.

BACKGROUND: Gestational hypertension (GH) remains one of the main causes of high maternal and perinatal morbidity and mortality worldwide with the highest incidence among primigravidae of about 10%-15%. However, it was noted that the incidence of GH in primigravidae who conceived following assisted reproductive technique (ART) or intrauterine insemination (IUI) supplemented with dydrogesterone during the first trimester was low. AIM: To determine whether dydrogesterone supplementation during the first trimester can reduce the incidence of GH among primigravidae. METHOD: A prospective cross-sectional comparative study was undertaken in 2010 on 116 primigravidae (study group) who conceived following ART or IUI and supplemented with dydrogesterone up to 16 weeks gestation. They were matched for age and race at 16 weeks gestation with a control patient from the early pregnancy clinic who were primigravidae (n = 116) who conceived spontaneously without dydrogesterone supplementation. FINDINGS: The incidence of GH in the study group was significantly lower than the control group (1.7% versus 12.9%, p = 0.001). The incidence of fetal distress was also significantly lower in the study group compared to the control group (4.3% versus 18.1%, p = 0.001). INTERPRETATION: Dydrogesterone supplementation during the first trimester significantly reduced the incidence of GH and fetal distress in primigravidae.

Implementation of certified endometriosis centers: 5-year experience in German-speaking Europe.

The idea of quality improvement in the management of endometriosis has been brought to attention throughout Europe. This - first and foremost - includes the implementation of centers specialized in treating endometriosis. This leads to qualification of both physicians and other medical staff, enforcement of research efforts, and informing the patients, the public, politicians, healthcare providers, and industry. Given limited budgets, focusing on the existing national commitment may be the first step.

Managing immunity in resistant cancer patients correlates to survival: results and discussion of a pilot study.

Many cancer patients do not die due to impaired organ functions, but as a result of reduced general conditions, such as cachexia, sarcopenia, depression, infections, or stress. Reduced general health may be caused by immune modifying cytokines released from the tumor into the body. Improvement of immunity would not only reduce cancer side effects through inhibiting cytokine release from the tumor into the blood, but also, according to a new hypothesis, modify the cancer stem cells (CSC) in the tumor, which are believed to drive cancer growth and metastasis. We reported previously several investigations with a dietary fermented soy formulation (FSWW08) in cancer patients, where we saw a) strong reduction of cancer symptoms, b) broken resistance to chemotherapy, and c) a strong reduction of chemotherapy's toxic side effects, when taken in combination. This publication reports two new findings from a pilot study with postsurgical, treatment resistant patients conducted over four years. First, neither treatment resistance nor side effects were observed. Second, more patients have survived than expected. The improved health and immunity is detected together with increased CSC differentiation, suggesting lower aggressiveness, which was corroborated by increased gene expressions, particularly of steroidal hormones, MAPkinase, NF-κB, and tumor suppressor factor p53, a typical marker of "stemness" or cell differentiation. Although limited by its small, homogenous sample size, the results of this pilot study illustrate the relationship between CSCs differentiation, and the clinical symptoms of immunity, which influence survival outcomes and raise the clinical potential of measuring CSCs in ovarian, prostate, and breast cancers. The improved survival rates are also seen in larger cohort studies, which show similar gene expression profiles, which were induced by FSWW08 in the treatment resistant cancer patients in this study.

Non-contraceptive benefits of hormonal contraceptives.

Besides the contraceptive effect of the various hormonal contraceptives, it is intended to demonstrate the non-contraceptive health benefits for treatment and prevention of bleeding problems, menstruation-related pain and other disorders, such as premenstrual syndrome and signs of androgenization. The effectiveness can be improved by choosing the proper progestogen with antiandrogenic action. Treatment but also prevention can be achieved with hormonal contraceptives in benign proliferative diseases of women, such as ovarian cysts, endometriosis, adenomyosis, endometrial hyperplasia, myoma and benign breast disease. Furthermore, hormonal contraceptives such as estrogen/progestogen combinations reduce pelvic inflammatory disease, rheumatoid arthritis, asthma symptoms and preserve bone density. In addition, a major impact in oncological prevention seems to be possible for ovarian, endometrial and colon cancer and these positive preventive effects seem to persist also after discontinuation of hormonal contraceptives. In addition, practical concepts for hormonal contraceptive selection will be outlined.

[Antibiotic prophylaxis in cesarean section -- piperacillin versus piperacillin/tazobactam in 300 cesarean sections]. / Antibiotikaprophylaxe bei Sectio Caesarea -- Piperacillin 4 g versus Piperacillin/Tazobactam 4.5 g.

INTRODUCTION: Antibiotic prophylaxis is a standard procedure in obstetric surgery and has been discussed in various investigations. Use of treatment is judged by high efficacy and good tolerance. METHOD: In 300 patients undergoing cesarean sections we compared results of application of Piperacillin 4 g and Piperacillin/Tazobactam 4.5 g after cut of umbilical cord. Tazobactam/Piperacillin is a combination of a broad-spectrum penicillin and a beta-lactamase inhibitor with increased toxicity against staph. aureus, enterobacter, and other germs responsible for local and systemic infections in obstetric surgery. RESULTS: We did not observe any severe adverse effects. Rate of severe wound infections was 1.3 % (Tazobactam/Piperacillin) and 2 % (Piperacillin alone). The difference showed no statistic significance (p > 0.01). During postoperative course we found a higher increase of CRP (p < 0.01) in the Piperacillin group. CRP proved to be a useful objective parameter to distinguish between patients with or without postoperative infections. No differences were found in the number of leucocytes, time in hospital and other parameters.

High-dose pilot study with the novel progestogen dienogestin patients with endometriosis.

High-dose dienogest (20 mg/day) was used for the treatment of endometriosis in women aged 18-52 years after laparoscopic and histological diagnosis of endometriosis and staging according to the revised American Fertility Society criteria. Treatment efficacy was analyzed objectively by second-look laparoscopy, and serum hormone measurements and evaluation of endometriosis-related symptoms were performed done and side-effects recorded. Compared with other high-dose progestin therapies, treatment with dienogest was shown to be effective even in stage IV endometriosis. The side-effect profile of the high-dose dienogest treatment appears to be highly favorable compared with other treatments. Neither the menopausal symptoms caused by therapy with gonadotropin-releasing hormone agonists nor the adverse androgen-related effects induced by danazol were observed. Therefore, long-term high-dose dienogest therapy can be recommended particularly for women with progressive endometriosis.

WITHDRAWN: The safety of synthetic paclitaxel by intralesional delivery with OncoGeltrade mark into skin breast cancer metastases: method and results of a clinical pilot trial.

Ahead of Print article withdrawn by publisher

Prevention and treatment of pregnancy-induced hypertension (preeclampsia) with progestogens.

Available data indicate that progesterone is able to treat pregnancy-induced hypertension (preeclampsia). Dydrogesterone and 17alpha-hydroxyprogesterone caproate might also be used for this purpose. Prevention of hypertensive disorders in preeclampsia also seems possible, but studies are needed to confirm this.

[ENZIAN-score, a classification of deep infiltrating endometriosis]. / ENZIAN-Score, eine Klassifikation der tief infiltrierenden Endometriose.

The ENZIAN-Score is presented as a new instrument to classify the deep infiltrating endometriosis. Especially the retroperitoneal part of the severe endometriosis is focussed on. In analogy to an oncological staging four different stages are pronounced. The localisation and the expansion of the endometriosis nodule was indicated to different subgroups. The still used rAFS-score is of no clinical evidence, as we pointed out in a retrospective study of our patients with severe intestinal endometriosis.

Pathophysiology, diagnosis and treatment of endometriosis.

Endometriosis is generally a benign condition. However, there is a tendency towards progression and in part deep infiltrating processes occur, which can lead to obstruction and even silent loss of organ function such as kidney failure. Hereditary, genetic and immunological peculiarities have been found. Important are symptoms such as pain and infertility, which burden the life of the women involved. In spite of extensive research in the past the pathogenesis and epidemiology of the disease are not definitely clarified as yet. The estimated prevalence of endometriosis ranges between 10% and even more than 50% depending on the underlying problems of the women studied. Besides the main location of the disease within the pelvis also extra pelvic locations have been found (lung, lymph nodes, scars). The diagnosis should be established by histological verification. The main therapeutic modalities consist of surgery and medical treatment or combinations, which need to be individually adjusted, because of the high risk of recurrence and progression of the disease. The aim should be early detection and treatment as complete as possible, since symptom relief, resolution or prevention of infertility and decrease of recurrences are at their best under these circumstances.

[Prevention of preterm delivery with gestagens]. / Prävention der Frühgeburtlichkeit durch Gestagene.

Preterm delivery with its short-term and long-term sequealae constitutes a serious problem in terms of morbidity, disability and mortality of the newborn and cost to the society. The incidence of premature deliveries persists and according to the latest national and international reports a tendency for an increase has been observed. Therefore, besides screening programmes for the detection of vaginal infections one has to look for additional therapeutic concepts. According to previous data and recent publications, progesterone vaginally and 17alpha-hydroxyprogesterone caproate intramuscularely should be considered as possible treatment options for the prevention of preterm delivery in high-risk women, with therapy starting in the second trimester.

The human chorionic gonadotropin molecule from patients with trophoblastic diseases has a high thyrotropic activity but is less active in the ovary.

To examine the pathogenesis of hyperthyroidism in women with trophoblastic diseases, the biological activity of human chorionic gonadotropin (hCG) molecules in women with normal pregnancy (n = 85) and in women with trophoblastic diseases (vesicular mole, n = 30; and choriocarcinoma, n = 12) was compared. Hyperthyroidism (thyroid stimulating hormone (TSH) < 0.3 mIU/l) was observed more frequently in women with trophoblastic diseases. All the sera were then subjected to Chinese hamster ovary cells transfected with the human TSH receptor (CHO-hTSHr cells) and cAMP production was compared. Sera from the women with choriocarcinoma showed the highest cAMP production. Interestingly, significant correlation between serum hCG level and cAMP production in CHO-hTSHr cells was observed only in women with trophoblastic disease. All the sera were then applied to CHO cells transfected with hCG/luteinizing hormone (LH) receptor (CHO-hCG/LHr cells). In contrast to the findings with the TSH receptor, sera from the women with normal pregnancy showed the highest cAMP production in these cells. Correlation between serum hCG level and cAMP production in CHO-hCG/LHr cells was significant only in normal pregnancy. These results indicate that the hCG molecule from women with trophoblastic diseases displays enhanced thyrotropic activity.

The prognostic value of serum inhibin, 17 beta-estradiol and progesterone in cases of hydatidiform mole.

The purpose of this study was to provide a diagnostic and a prognostic variable that could easily be measured in the laboratory, and that would predict the need for future therapy of persistent gestational trophoblastic disease. There would no longer be a need to treat all cases of hydatidiform mole prophylactically, to improve the outcome in only about 20% predicted to develop malignant gestational trophoblastic tumors. Circulating beta-human chorionic gonadotropin (beta-hCG), progesterone, 17 beta-estradiol and inhibin levels were measured using standard radioimmunoassays in 60 patients with complete hydatidiform mole and in 20 normal pregnant women of a corresponding duration of pregnancy and having a maternal indication for therapeutic abortion. There were no significant statistical differences between the two groups as regards gravidity, parity and gestational age. There was a significant statistical difference between patients with a molar pregnancy who developed gestational trophoblastic tumors (GTT) and those who did not develop GTT as regards pre-evacuation and follow-up mean serum beta-hCG, mean serum progesterone and mean serum 17 beta-estradiol levels. These findings together with the persistently elevated mean serum progesterone and mean serum 17 beta-estradiol levels at 6 weeks after evacuation in all cases who developed GTT suggested that progesterone as well as 17 beta-estradiol serum levels might be of prognostic value in cases of molar pregnancy. However, larger numbers of cases are required to correlate findings to beta-hCG serum level. Although mean serum inhibin level was significantly higher in women with hydatidiform mole than in normal pregnant women, it lacks any prognostic value for detection of subsequent gestational trophoblastic tumors.

First trimester endocrinology: consequences for diagnosis and treatment of pregnancy failure.

First-trimester endocrinology is determined on the one hand by corpus luteum progesterone and estradiol biosynthesis and secretion and on the other hand by the time of onset and extent of progesterone and estradiol secretion by the placenta. This dual interplay is dominated by the corpus luteum placental shift, where a relative progesterone and estradiol deficiency can develop and may lead to early as well as late abortion. Measurements of serum progesterone and estradiol are mandatory in order to reveal such deficiencies and to treat them effectively with 17 alpha-hydroxyprogesterone caproate in combination with estradiol valerate or with progestins such as dydrogesterone.

Gonadotropin-releasing hormone agonists for prevention of postoperative adhesions: an overview.

Adhesion formation is of major concern to the pelvic surgeon. Most patients develop postoperative adhesions regardless of whether the mode of access to the abdominal cavity is by laparoscopy or laparotomy. Infertility is related to adhesions in the pelvis in 15-20% of cases. Peritoneal adhesions are the main cause of mechanical bowel obstruction in 65-80% of cases and contribute to a large extent to health-care expenditures. To prevent the formation of postoperative adhesions, a variety of medications have been studied such as glucocorticoids, heparin, dextran 70, saline solution, antibiotics, promethazine, antihistamines, prostaglandin synthesis inhibitors, Ringer's lactate solution, calcium-channel blockers and barriers such as Interseed and Gore-Tex. Such adhesions can be induced when operating on myomas and endometriosis. Experimental and clinical studies have demonstrated various mechanisms of action to be involved in adhesion prevention when gonadotropin-releasing hormone agonists (GnRH-a) are used for treatment. The following have been demonstrated and suggested: (1) Hypoestrogenic condition was found in rats to be associated with decreased adhesion formation. This could be related to the influence on estrogen-dependent growth factors and growth modulators by reliable and constant inhibition of ovarian estradiol biosynthesis and secretion, but also non-competitive estrogen antagonism seems to play a role. (2) Treatment with GnRH-a reduces the growth hormone release stimulated by growth hormone-releasing hormone. (3) GnRH-a treatment influences neoangiogenesis by affecting vascular endothelial growth factor and basic fibroblastic growth factor. (4) GnRH-a reduce the basal rate of coagulatory processes. The frequency and extent of fibrin-generating and degrading processes are reduced. Activity of the plasminogen activating inhibitor is reduced, suggesting an improvement infibrinolytic reactivity. (5) GnRH-a use alters the vascular resistance index, pulsatility index and vascular peak velocity, and possible immune response. (6) Avoidance of bleeding can reduce fibrin and therefore decreases the matrix for invasion by fibroblasts. (7) GnRH-a reduce the degree of inflammation postoperatively. Adhesion prevention seems to be at its best when pre- and postoperative GnRH-a treatment is administered. At present, there are trends to operate without prior treatment with GnRH-a. Based upon the data available, it seems worthwhile to consider preoperative and also postoperative treatment with GnRH-a: pretreatment for at least 2-3 months seems to be indicated, and a similar time after operation, to block the events associated with adhesion formation.

Evaluation of tumour markers in molar pregnancy.

METHODS: Circulating CA 125, CA 19-9, CA 15-3 and carcinoembryonic antigen (CEA) levels were studied in sixty patients with hydatidiform mole and in twenty normal pregnant women of a corresponding duration of pregnancy. DISCUSSION: Serum levels of CA 125, CA 15-3 and CEA are not affected by molar pregnancy. The mean level of CA 19-9 in maternal serum is significantly lower in cases of molar pregnancy when compared with cases of normal pregnancy. The amnion cell origin of CA 19-9 could explain the statistically significant difference between cases of therapeutic abortion and cases of HM (complete HM lacks amniotic membrane).

Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.

BACKGROUND: Capecitabine is a rationally designed oral, tumor-activated fluoropyrimidine carbamate with high activity in metastatic breast cancer. This multicenter phase II study was designed to evaluate further the efficacy and safety of capecitabine in patients with metastatic breast cancer previously treated with a taxane-containing regimen. PATIENTS AND METHODS: All patients had to have documented progression after paclitaxel- or docetaxel-containing chemotherapy. Treatment comprised 3-week cycles of oral capecitabine 1250 mg/m(2) twice-daily for 14 days followed by a 7-day rest period. RESULTS: One hundred and thirty-six patients were enrolled. Disease stabilization occurred in 63 patients (46%) and the overall response rate was 15% (95% confidence interval 10% to 23%), providing an overall tumor control rate of 62%. Median time to progression was 3.5 months, median duration of response was 7.5 months and median overall survival was 10.1 months. Capecitabine was generally well-tolerated: most treatment-related adverse events were grade 1/2 in intensity; grade 3/4 treatment-related adverse events were hand-foot syndrome (13%), diarrhea (8%), vomiting (4%) and nausea (3%). There were no treatment-related deaths. CONCLUSIONS: This study confirms that capecitabine achieves a high tumor control rate in heavily pretreated patients with metastatic breast cancer. Due to its favorable safety profile and convenient oral administration, capecitabine can be given as an outpatient therapy. Capecitabine should be considered the reference treatment in this setting based on consistently high efficacy and good tolerability.