Eva-Katrin Bentz

Side effects of phytoestrogens: a meta-analysis of randomized trials.

BACKGROUND Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown. METHODS Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials. RESULTS We identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P=.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P=.003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups. CONCLUSIONS Based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies.

Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy

OBJECTIVE To evaluate the incidence of venous thromboembolism (VTE) in transsexual patients and the value of screening for thrombophilia in this population. DESIGN Retrospective cohort study. SETTING Academic research institution. PATIENT(S) Two hundred fifty-one transsexuals (162 male-to-female [MtF] and 89 female-to-male [FtM] transsexuals). INTERVENTION(S) Screening for activated protein C (aPC) resistance, antithrombin III, free protein S antigen, and protein C deficiency. MAIN OUTCOME MEASURE(S) Incidence of thrombophilic defects and VTE during cross-sex hormone therapy. RESULT(S) Activated protein C resistance was detected in 18/251 patients (7.2%), and protein C deficiency was detected in one patient (0.4%). None of the patients developed VTE under cross-sex hormone therapy during a mean of 64.2 +/- 38.0 months. There was no difference in the incidence of thrombophilia comparing MtF and FtM transsexuals (8.0% [13/162] vs. 5.6% [5/89], respectively). CONCLUSION(S) VTE during cross-sex hormone therapy is rare. General screening for thrombophilic defects in transsexual patients is not recommended. Cross-sex hormone therapy is feasible in MtF as well as in FtM patients with aPC resistance.

Methylenetetrahydrofolate Reductase C677T Polymorphism and Pregnancy Complications

OBJECTIVE: To investigate the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with intrauterine fetal death, preeclampsia, preterm delivery, and small for gestational age (SGA) infants. METHODS: In a prospective cohort study, DNA from 2,000 pregnant women were analyzed for MTHFR C677T by DNA microarray (wild-type allele, C; mutant allele, T). RESULTS: One thousand six hundred seventy-five women completed the study. Of these, 16.6% (278 women with 556 genetic alleles) developed at least one pregnancy complication and were designated study cases. There were 1,397 women (with 2,794 genetic alleles) who served as controls. MTHFR C677T allele frequencies were significantly different between cases and controls (C [wild-type]: 346 of 556 [62%]; T [mutant]: 210 of 556 [38%] compared with C: 1,911 of 2,794 [68%]; T: 883 of 2,794 [32%]; P=.005; odds ratio [OR] 1.23, 95% confidence interval [CI] 1.06–1.42). Genotype distributions were also different between cases and controls (C/T+T/T [abnormal]: 174 of 278 [63%]; C/C [normal]: 104 of 278 [37%] compared with C/T+T/T: 728 of 1,397 [52%]; C/C 669 of 1,397 [48%]; P=.002; OR 1.54, 95% CI 1.18–2.02). The clinical effect of the MTHFR C677T polymorphism was restricted to women with SGA infants (P=.05; OR 1.33, 95% CI 1.00–1.77). No significant differences in genotype distributions were observed among women with intrauterine fetal death, preeclampsia, and preterm delivery. CONCLUSION: MTHFR C677T is a genetic marker for identifying women at increased risk of SGA infants. LEVEL OF EVIDENCE: II

Ten estrogen- related polymorphisms and endometriosis : A study of multiple gene-gene interactions

OBJECTIVE: Genetic as well as hormonal factors are known to influence the development and clinical course of endometriosis. We aimed to investigate the association among 10 single nucleotide polymorphisms (SNPs) involved in the estrogen metabolism and endometriosis and to develop a multiple genetic model. METHODS: In a case–control study, we investigated the genotype frequencies of 10 estrogen metabolizing SNPs in 32 patients with endometriosis and 790 healthy controls using sequencing-on-chip-technology with solid-phase polymerase chain reaction on oligonucleotide microarrays: catechol-O-methyltransferase, Val158Met G->A, 17-β-hydroxysteroid dehydrogenase type 1 (HSD17), vlV A->C, cytochrome P450 (CYP), 17 A2 allele T->C, CYP1A1 MspI RFLP T->C, CYP1A1 Ile462Val A->G, CYP19 Arg264Cys C->T, CYP19 C1558T C->T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor alpha IVS1 –401>C. Associations and 2-way interaction models between SNPs were calculated by stepwise logistic regression models. RESULTS: In a univariate model, HSD17 vlV A->C was associated with a significantly increased risk of endometriosis (P = .004; odds ratio 3.9, 95% confidence interval 1.6–9.8). When all 2-way interactions of investigated SNPs were ascertained, no significant interactions among SNPs were observed. In a multivariate model, HSD17 vlV A->C was also significantly associated with endometriosis (P = .002). CONCLUSION: We present data on multiple SNPs in patients with endometriosis indicating an association between HSD17 gene variation and the disease. Although not able to demonstrate interaction models of SNPs, we provide evidence of HSD17 vlV A->C as a low penetrance genetic marker of endometriosis. LEVEL OF EVIDENCE: II-2

A Common Polymorphism of the SRD5A2 Gene and Transsexualism

The relation between genetic variation of the androgen metabolism and transsexualism is unknown. In a case-control study of 100 male-to-female (MtF) transsexuals, 47 female-to-male (FtM) transsexuals, and 1670 controls, the authors assess allele and genotype frequencies of the steroid 5-α reductase (SRD5A2) Val89Leu polymorphism using polymerase chain reaction. Allele and genotype frequencies are not significantly di ferent between MtF transsexuals and male controls (SRD5A2 V: 137/200 [69%] and SRD5A2 L: 63/200 [31%] vs 1065/1510 [71%] and 445/1510 [29%], respectively; P = .6; odds ratio [OR], 1.10; 95% confidence interval [CI], 0.76-1.58; SRD5A2 V/V+V/L: 92/100 [92%] and L/L 8/100 [8%] vs SRD5A2 683/755 [91%] and 72/755 [9%], respectively, P = .7; OR, 0.82; 95% CI, 0.24-2.84). Allele and genotype frequencies are also not significantly di ferent between FtM transsexuals and female controls (SRD5A2 V: 70/94 [74%] and SRD5A2 L: 24/94 [26%] vs 1253/1830 [69%] and 573/1830 [31%], respectively; P = .3; OR, 0.75; 95% CI, 0.45-1.26; SRD5A2 V/V+V/L: 44/47 [93%] and L/L 3/47 [7%] vs 823/915 [90%] and 92/915 [10%], respectively, P = .6; OR, 0.61; 95% CI, 0.11-3.32). Of note, there is no gender-specific genotype distribution among controls. The SRD5A2 Val89Leu SNP is not associated with transsexualism, refuting SRD5A2 as a candidate gene of transsexualism.

Non-contraceptive benefits of oral contraceptives

Background: There is increasing awareness of the opportunity that many contraceptive interventions may provide for additional health benefits. However, treatment of medical problems with oral contraceptives (OCs) is often an ‘off-label’ practice. Objective: The aim of this review is to summarize available data on non-contraceptive benefits of OCs. Methods: Review of the literature. Results: OCs have been shown to reduce the risk of ovarian, endometrial, and colorectal cancer. It has been suggested that OCs may be used in treatment of endometriosis, menorrhagia, and uterine leiomyomas. Pelvic inflammatory disease, dysmenorrhea, premenstrual syndrome, and acne have been shown to improve under OCs. Conclusion: OCs are important for global and female health. Besides contraception, non-contraceptive effects of OCs are evidence based, well established, and commonly used in clinical practice.

OCT-4 expression in follicular and luteal phase endometrium: a pilot study

BackgroundThe stem cell marker Octamer-4 (OCT-4) is expressed in human endometrium. Menstrual cycle-dependency of OCT-4 expression has not been investigated to date.MethodsIn a prospective, single center cohort study of 98 women undergoing hysteroscopy during the follicular (n = 49) and the luteal (n = 40) phases of the menstrual cycle, we obtained endometrial samples. Specimens were investigated for OCT-4 expression on the mRNA and protein levels using reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Expression of OCT-4 was correlated to menstrual cycle phase.ResultsOf 89 women sampled, 49 were in the follicular phase and 40 were in the luteal phase. OCT-4 mRNA was detected in all samples. Increased OCT-4 mRNA levels in the follicular and luteal phases was found in 35/49 (71%) and 27/40 (68%) of women, respectively (p = 0.9). Increased expression of OCT-4 protein was identified in 56/89 (63%) samples. Increased expression of OCT-4 protein in the follicular and luteal phases was found in 33/49 (67%) and 23/40 (58%) of women, respectively (p = 0.5).ConclusionsOn the mRNA and protein levels, OCT-4 is not differentially expressed during the menstrual cycle. Endometrial OCT-4 is not involved in or modulated by hormone-induced cyclical changes of the endometrium.

Gene expression signatures of breast tissue before and after cross-sex hormone therapy in female-to-male transsexuals.

OBJECTIVE To evaluate gene expression signatures of breast tissue in female-to-male (FtM) transsexuals under cross-sex hormone therapy (HT). DESIGN Prospective cohort study. SETTING Academic research institution. PATIENT(S) Five hormone-naïve FtM transsexuals before and after HT. INTERVENTION(S) Breast tissue biopsy before and after 2 years of intramuscular testosterone undecanoate (1,000 mg every 12 wk) and oral lynestrenole (5 mg daily), and gene signature analysis by global gene expression array covering 28,869 genes. MAIN OUTCOME MEASURE(S) Differential regulation of specific genes and gene expression signatures. RESULT(S) We identified 2,250 differentially expressed probe sets. One hundred twenty probe sets showed >2-fold change, of which 77 (64.2%) were up-regulated and 43 (35.8%) down-regulated. Genes involved in transcription were most overrepresented, with 43 out of 97 (44.3%) annotated probes, e.g., the transcription factor complex activator protein 1, including all three Jun genes (c-Jun, JunB, and JunD), two Fos genes (c-Fos and FosB), and activating transcription factor 3. In a Database for Annotation, Visualization, and Integrated Discovery analysis of the 2,007 down-regulated probe sets, proteins of the ribosome pathway and of two pathways involved in protein degradation, i.e., proteasome- and ubiquitin-mediated proteolysis, were significantly down-regulated. We identified eight breast cancer-associated gene expression signatures significantly overlapping with differentially regulated probe sets after cross-sex HT. CONCLUSION(S) Cross-sex HT in FtM transsexuals leads to the up-regulation and down-regulation of 243 and 2,007 distinct genes, respectively, and is associated with breast cancer-related gene expression signatures.

Intrauterine Fetal Death and Delivery Complications Associated with Coagulopathy: A Retrospective Analysis of 104 Cases

OBJECTIVE To assess the prevalence of delivery complications associated with coagulopathy in women with intrauterine fetal death (IUFD). METHODS This is a retrospective cohort study of women with IUFD at >24 weeks gestation or a birth weight of >500 g between 1994 and 2007. Clinical data were assessed by chart review. RESULTS One hundred four women were diagnosed with IUFD. The mean time between diagnosis of IUFD and delivery was 28.8 (+/-17.4) hours. Twelve of 104 (11.5%) women had a delivery complication associated with coagulopathy, defined as need for blood transfusion. In 8 of these 12 women, coagulopathy was associated with a preexisting preeclampsia/hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome, uterine rupture after induction, or an acute clinical problem at presentation to the clinic. In 4 of 104 (4%) women, there was no attributable cause of coagulopathy other than IUFD. In these women, there was a statistically significant difference of laboratory parameters of coagulation at the time of diagnosis of IUFD compared with women who did not subsequently develop coagulopathy; platelet count 93.3 +/- 96.4 vs. 229.3 +/- 68.1 G/L, p < 0.001; prothrombin time (PT) 97.0 +/- 43.9 vs. 123.3 +/- 21.1 %, p = 0.02; activated partial thromboplastin time (aPTT) 42.9 +/- 34.0 vs. 31.5 +/- 4.3 sec, p = 0.01; thrombin time (TT) 22.8 +/- 16.5 vs. 14.1 +/- 13.3 sec, p = 0.02), plasma fibrinogen 219.0 +/- 117.5 vs. 472.9 +/- 122.8 mg/dL, p < 0.001), and antithrombin III 70.5 +/- 21.9 vs. 101.5 +/- 17.0 %, p = 0.01. CONCLUSIONS Delivery complications associated with coagulopathy occur in 11% of women with IUFD and are associated with preexisting preeclampsia/HELLP, uterine rupture, or an acute clinical problem in most cases. In 4% of women with IUFD, coagulopathy develops without an apparent cause.

Ten Polymorphisms of Estrogen-Metabolizing Genes and a Family History of Colon Cancer—An Association Study of Multiple Gene-Gene Interactions:

Estrogen replacement therapy is associated with a reduced risk of colon cancer. Therefore, we evaluated the following ten estrogen metabolism-associated single-nucleotide polymorphisms (SNPs) by sequencing-on-chip technology using solid-phase polymerase chain reaction (PCR) on oligonucleotide microarrays: catechol-O-methyltransferase (COMT) Val158Met G→A, 17-beta-hydroxysteroid dehydrogenase type 1 (HSD17) vlV A→C, cytochrome P-450 (CYP) 17 A2 allele T→C, CYP1A1 MspI RFLP f→C, CYP1A1 Ile462Val A→G, CYP19 Arg264Cys C→T, CYP19 C1558T C→T, CYP 1B1 Leu432Val, CYP1B1 Asn453Ser, and estrogen receptor (ER) alpha IVS1 - 401→C in 76 patients with a family history of colon cancer and 722 healthy controls. Using stepwise logistic regression models, we found that none of the investigated SNPs is associated with a family history of colon cancer in a univariate and multivariate logistic regression model. In addition, when all two-way interactions of the investigated SNPs were ascertained, no significant interactions between SNPs were observed. In conclusion, we found no association between the carriage of one or multiple SNPs of the estrogen metabolism and a family history of colon cancer.