Thomas Strowitzki

Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial

BACKGROUND Dienogest is a selective progestin that has been investigated in a clinical trial programme for the treatment of endometriosis. The current non-inferiority trial compared the efficacy and safety of dienogest against leuprolide acetate (LA) for treating the pain associated with endometriosis. METHODS Patients with confirmed endometriosis were randomized to treatment with dienogest (2 mg/day, orally) or LA (3.75 mg, depot i.m. injection, every 4 weeks) for 24 weeks. The primary efficacy variable was absolute change in pelvic pain from baseline to end of treatment, assessed by visual analogue scale (VAS). Safety variables included adverse event profile, laboratory parameters, bone mineral density (BMD), bone markers and bleeding patterns. RESULTS A total of 252 women were randomized to treatment with dienogest (n = 124) or LA (n = 128); 87.9 and 93.8% of the respective groups completed the trial. Absolute reductions in VAS score from baseline to Week 24 were 47.5 mm with dienogest and 46.0 mm with LA, demonstrating the equivalence of dienogest relative to LA. Hypoestrogenic effects (e.g. hot flushes) were reported less frequently in the dienogest group. As expected, bleeding episodes were suppressed less with dienogest than with LA. Changes in mean lumbar BMD between screening and final visit were +0.25% with dienogest and -4.04% with LA subgroups (P = 0.0003). Markers of bone resorption increased with LA but not dienogest. CONCLUSIONS Dienogest 2 mg/day orally demonstrated equivalent efficacy to depot LA at standard dose in relieving the pain associated with endometriosis, although offering advantages in safety and tolerability.

Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase.

OBJECTIVE To analyze if oocytes can be obtained in all patients before cancer treatment within 2 weeks by initiating ovarian stimulation during the follicular or luteal phase. DESIGN Prospective controlled multicenter trial. SETTING Four university-based centers. PATIENT(S) Forty cancer patients before chemotherapy. INTERVENTION(S) Twenty-eight patients were stimulated with gonadotropins in the follicular phase (group I). In 12 patients (group II), ovarian stimulation was initiated in the luteal phase, and these received GnRH antagonists and recombinant FSH. In 14 patients, 143 oocytes were further processed for fertilization by intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S) Number of oocytes aspirated after ovarian stimulation, cumulative FSH/hMG dosage, viability and maturity of oocytes, and fertilization rate by ICSI. RESULT(S) Patients in group I (age 27.6 +/- 4.9 yrs) were stimulated on average for 10.6 days, and patients in group II (age 31.2 +/- 5.7 yrs) for 11.4 days. Total amount of FSH was on average 2,255 IU (I) and 2,720 IU (II) per patient. Average and median numbers of aspirated oocytes were, respectively, 13.1 and 11.5 (I) versus 10.0 and 8.5 (II); 83.7% (I) and 80.4% (II) of the oocytes were mature and viable and could be treated by ICSI. Fertilization rate was 61.0% (I) versus 75.6% (II). CONCLUSION(S) This pilot study suggests that oocytes can be obtained before cancer treatment efficiently irrespective of the phase of the menstrual cycle.

Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study

OBJECTIVE To investigate the efficacy and safety of oral dienogest 2mg compared with placebo in the treatment of endometriosis-associated pelvic pain (EAPP). STUDY DESIGN This was a 12-week, randomized, double-blind, placebo-controlled, multicenter (n=33) study in Germany, Italy, and Ukraine of 198 women aged 18-45 years with laparoscopically confirmed endometriosis and EAPP score > or =30 mm on a visual analog scale (VAS). Dienogest 2mg or placebo was administered orally once daily. The primary efficacy variable was absolute change in EAPP from baseline to Week 12, as determined by the target variables of change in VAS score and change in intake of supportive analgesic medication (ibuprofen) for pelvic pain. RESULTS Mean reductions in VAS score between baseline and Week 12 in the full analysis set were 27.4 mm and 15.1mm in the dienogest and placebo groups, respectively-a significant score difference of 12.3 mm in favor of dienogest (P<0.0001). Changes in intake of supportive analgesic medication were modest in both groups. The primary efficacy measure of absolute change in EAPP demonstrated the superiority of dienogest over placebo. Dienogest was generally well tolerated and few adverse events were associated with therapy. CONCLUSIONS Dienogest at a dose of 2mg daily for 12 weeks was significantly more effective than placebo for reducing EAPP.

Testosterone and 5α-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines

Androgens are of biological and clinical importance for the growth and development of breast cancer in women, and the androgen receptor (AR) has been shown to be a predictor of tumor differentiation. In the present study, we investigated the relationship between AR status and testosterone and 5α-dihydrotestosterone (DHT)-dependent proliferation of the human breast carcinoma cell lines MCF-7, T47-D, MDA-MB 435S and BT-20. AR status was studied by means of immunocytochemistry and Western blot analysis. All four cell lines stained positively for AR. Western blot analysis revealed a strong expression of AR in MCF-7, in contrast to BT-20 cells. According to proliferation kinetics, we observed a significant (p ≤ 0.05) dose-dependent inhibition of cell growth by testosterone and DHT treatment in all four cell lines. In the estrogen receptor (ER)-negative cell lines BT-20 and MDA-MB 435S, testosterone was a more potent inhibitor of cell proliferation than DHT (p ≤ 0.05), in contrast to the ER-positive cells lines MCF-7 and T47-D, in which a stronger inhibition of proliferation was achieved by DHT. A partial transformation of testosterone to estrogen in ER-positive cells might be an explanation for this effect. Our data favor a possible role of androgens in growth regulation of breast cancer. Clinical studies are needed to analyze the importance of AR as a possible predictor in response to endocrine therapy of breast cancer.

PREGNANCY COMPLICATIONS, OBSTETRIC RISKS, AND NEONATAL OUTCOME IN SINGLETON AND TWIN PREGNANCIES AFTER GIFT AND IVF

PurposeIn vitro fertilization (IVF) and to a lower extent gamete intra-fallopian transfer (GIFT) have become routine infertility treatments in industrialized countries. Our purpose is to compare the obstetric and neonatal characteristics of singleton and twin pregnancies after GIFT and IVF with those conceived spontaneously.MethodsThis case-control study was conducted in a tertiary care medical center. The 322 singleton and 78 twin pregnancies after GIFT or IVF from 1991 through 1996 were evaluated and compared with each other, and with a control group that conceived spontaneously and matched for parity, maternal and gestational age. Statistical significance of differences was assessed by χ2 test or two-tailed Fisher exact test. Continuous variables were compared by the paired t-test.ResultsPregnancy-induced hypertension (PIH) and vaginal bleeding were significantly more frequent maternal complications in the GIFT/IVF singleton groups compared to controls. In twin pregnancies the rate of cesarean sections, vaginal bleeding and preterm labor were more common after GIFT/IVF but did not reach statistical significance. Assisted reproduction was associated with low birth weight only in twin pregnancies when controlled for confounding variables, however perinatal outcome was comparable. There was no significant difference in the outcome measures between GIFT and IVF pregnancies.ConclusionAfter controlling for parity, maternal and gestational age, singleton pregnancies conceived by GIFT/IVF are at increased obstetrical risk, however the perinatal outcome is comparable despite a lower average birth weight.

New approaches to embryo selection

Embryo selection has been an important topic since the introduction of assisted reproduction, with embryo morphology being the most obvious criterion. Although morphology serves as indicator for overall IVF laboratory quality, its statistical assessment limits the possibility to identify the most implantation-competent embryos. In order to reach a direct picture of the developing embryo, invasive procedures such as preimplantation genetic screening or transcriptome and proteome analysis of biopsied embryonic tissue were initially prioritized and are still under investigation. More recently, focus has shifted towards noninvasive techniques that maintain the integrity of the embryo. Metabolomic profiling of culture medium from growing embryos attracted much research. Although successful in a pilot study, that approach failed in a randomized controlled trial. Other metabolomics studies are on their way but not yet available for routine clinical use. The most promising strategy at present is the combined evaluation of morphology and developmental kinetics using time-lapse imaging. This has brought new insights into certain characteristics that enable deselection of embryos at an early stage of development and to identify others with high potential for successful implantation. However, there is still considerable room for improvement. Further strategies will most likely involve the combination of several different approaches.

Comparison of Efficacy, Cycle Control, and Tolerability of Two Low-dose Oral Contraceptives in a Multicenter Clinical Study

This study compares the contraceptive reliability, cycle control, and tolerability of two oral contraceptive preparations containing 20 micrograms of ethinyl estradiol combined with either 75 micrograms of gestodene (EE/GSD) or 150 micrograms of desogestrel (EE/DSG). Women received the trial preparations daily for 21 days, followed by a 7-day pill-free interval. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of 12 cycles. Efficacy data of 14,700 treatment cycles (EE/GSD: 7299; EE/DSG: 7401) were obtained from 1476 women (EE/GSD, n = 740; EE/DSG, n = 736). Both preparations provided effective contraception and good cycle control with a similarly low incidence of both spotting and breakthrough bleeding. The spotting rates in both treatment groups decreased from 35.1% (EE/GSD) and 37.5% (EE/DSG) in the first treatment cycle to approximately 10% in the fourth treatment cycle. The spotting incidence as percent of the total number of cycles was 12.7% for EE/GSD and 14.3% for EE/DSG. The breakthrough bleeding incidence was 5.2% of all cycles for EE/GSD and 6.0% of all cycles for EE/DSG. For 84.7% of the cycles in the gestodene group and for 82.5% of the cycles in the desogestrel group, neither spotting nor breakthrough bleeding were recorded. Overall, the spotting and breakthrough bleeding incidence tended to be lower with EE/GSD than with EE/DSG. However, the difference was not statistically significant. Amenorrhea was recorded in 2.7% of the cycles with EE/GSD and in 2.9% with EE/DSG. Both preparations were well tolerated and showed a similar pattern of adverse events. More than 83% of the women in both groups either did not gain weight or lost more than 2 kg. Both preparations had a beneficial effect on dysmenorrhea. Both regimens provided reliable contraception and good cycle control. The incidence of adverse events was relatively low and both preparations were well tolerated.

The degree of cycle irregularity correlates with the grade of endocrine and metabolic disorders in PCOS patients

OBJECTIVE PCOS (polycystic ovarian syndrome) is a clinically heterogeneous endocrine disorder which affects up to 4-10% of women of reproductive age. A standardized definition is still difficult because of a huge variety of different phenotypes. The aim of this study was to evaluate possible correlations between the degree of cycle irregularity and the grade of endocrine and metabolic abnormalities. STUDY DESIGN A cross-sectional study was carried out. Hyperandrogenic and/or hirsute women with regular menstrual cycles and polycystic ovaries on ultrasound (PCOS eumenorr, n=45), PCOS patients with oligomenorrhea (PCOS oligo, n=42) and PCOS patients with amenorrhea (PCOS amenorr, n=31) were recruited from the Department of Gynecological Endocrinology and Reproductive Medicine of the Womens University Hospital Heidelberg (Heidelberg, Germany). RESULTS Normocyclic patients demonstrated significantly better metabolic parameters (BMI, fasting insulin, HOMA-IR) than patients with oligo/amenorrhea. Hormonal parameters (LH, FSH, FAI and testosterone) were significantly different between patients with different menstrual patterns and patients with regular cycles. CONCLUSION Determining the degree of cycle irregularity as a simple clinical parameter might be a valuable instrument to estimate the degree of metabolic and endocrine disorders. Emphasis should be given to those parameters as a first step to characterize PCOS patients with a risk of endocrine and metabolic disorders leading to consequent detailed examination.

Resilience in infertile couples acts as a protective factor against infertility-specific distress and impaired quality of life

ObjectiveOur hypothesis was that resilience (=psychosocial stress-resistance) reduces infertility-specific distress and maintains quality of life of infertile couples.MethodsQuestionnaire data of WHO Quality of Life assessment (WHOQOL; domains: ‘physical’, ‘psychological’, ‘social relationships’ and ‘environment’), Fertility Problem Inventory (FPI; scales: ‘social concern’, ‘sexual concern’, ‘relationship concern’, ‘rejection of childfree lifestyle’ and ‘need for parenthood’), Resilience Scale (RS), as well as sociographic and medical data were available for 199 infertile couples.ResultsAge, medical diagnosis and ‘intensity of desire for a child’ had no influence on quality of life. High scores on ‘suffering from childlessness’ went along with less satisfaction on ‘physical’ and ‘psychological’ domains for the women only. For both partners, high scores on ‘suffering from childlessness’ went along with higher scores on all FPI scales. High resilience was associated with high scores on all WHOQOL domains for both partners, also with low scores on all FPI scales except for ‘need for parenthood’ for the women and with a low score only on ’relationship concern’ for the men.ConclusionsFor infertile couples, resilience can be considered as an unspecific protective factor against infertility-specific distress and impaired quality of life. When offering counselling to involuntarily childless couples, awareness should be raised for resilience as a couple’s resource and a “generic” factor of coping.

Polar Body Biopsy

Polar body biopsy combined with array comparative genomic hybridization allows detection of maternal chromosomal aberrations. Although it has limitations, it can be seen as an alternative to blastomere and trophectoderm biopsy.