[Show abstract][Hide abstract] ABSTRACT: Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity and is associated with pain and subfertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy.
To assess the effectiveness and safety of laparoscopic surgery in the treatment of painful symptoms and subfertility associated with endometriosis.
This review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group including searching CENTRAL, MEDLINE, EMBASE, PsycINFO, and trial registries from inception to July 2013.
Randomised controlled trials (RCTs) were selected in which the effectiveness and safety of laparoscopic surgery used to treat pain or subfertility associated with endometriosis was compared with any other laparoscopic or robotic intervention, holistic or medical treatment or diagnostic laparoscopy only.
Selection of studies, assessment of trial quality and extraction of relevant data were performed independently by two review authors with disagreements resolved by a third review author. The quality of evidence was evaluated using GRADE methods.
Ten RCTs were included in the review. The studies randomised 973 participants experiencing pain or subfertility associated with endometriosis. Five RCTs compared laparoscopic ablation or excision versus diagnostic laparoscopy only. Two RCTs compared laparoscopic excision versus diagnostic laparoscopy only. Two RCTs compared laparoscopic excision versus ablation. One RCT compared laparoscopic ablation versus diagnostic laparoscopy and injectable gonadotropin-releasing hormone analogue (GnRHa) (goserelin) with add-back therapy. Common limitations in the primary studies included lack of clearly-described blinding, failure to fully describe methods of randomisation and allocation concealment, and risk of attrition bias.Laparoscopic surgery was associated with decreased overall pain (measured as 'pain better or improved') compared with diagnostic laparoscopy, both at six months (odds ratio (OR) 6.58, 95% CI 3.31 to 13.10, 3 RCTs, 171 participants, I(2) = 0%, moderate quality evidence) and at 12 months (OR 10.00, 95% CI 3.21 to 31.17, 1 RCT, 69 participants, low quality evidence). Compared with diagnostic laparoscopy, laparoscopic surgery was also associated with an increased live birth or ongoing pregnancy rate (OR 1.94, 95% CI 1.20 to 3.16, P = 0.007, 2 RCTs, 382 participants, I(2) = 0%, moderate quality evidence) and increased clinical pregnancy rate (OR 1.89, 95% CI 1.25 to 2.86, P = 0.003, 3 RCTs, 528 participants, I(2) = 0%, moderate quality evidence). Two studies collected data on adverse events (including infection, vascular and visceral injury and conversion to laparotomy) and reported no events in either arm. Other studies did not report this outcome. The similar effect of laparoscopic surgery and diagnostic laparotomy on the rate of miscarriage per pregnancy was imprecise (OR 0.94, 95% CI 0.35 to 2.54, 2 studies, 112 women, moderate quality evidence).When laparoscopic ablation was compared with diagnostic laparoscopy plus medical therapy (GnRHa plus add-back therapy), more women in the ablation group reported that they were pain free at 12 months (OR 5.63, 95% CI 1.18 to 26.85, 1 RCT, 35 participants, low quality evidence).The difference between laparoscopic ablation and laparoscopic excision in the proportion of women reporting overall pain relief at 12 months on a VAS 0 to 10 pain scale was 0 (95% CI -1.22 to 1.22, P = 1.00, 1 RCT, 103 participants, low quality evidence).
There is moderate quality evidence that laparoscopic surgery to treat mild and moderate endometriosis reduces overall pain and increases live birth or ongoing pregnancy rates. There is low quality evidence that laparoscopic excision and ablation were similarly effective in relieving pain, although there was only one relevant study. More research is needed considering severe endometriosis, different types of pain associated with endometriosis (for example dysmenorrhoea (pain with menstruation)) and comparing laparoscopic interventions with holistic and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity. It is variable in both its surgical appearance and clinical manifestation, often with poor correlation between the two. Surgical treatment of endometriosis aims to remove visible areas of endometriosis and restore anatomy by the division of adhesions.
To assess the efficacy of laparoscopic surgery in the treatment of subfertility associated with endometriosis. The review aims to compare outcomes of laparoscopic surgical interventions compared to no treatment or medical treatment with regard to improved fertility.
We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (June 2009), Cochrane Central Register of Controlled Trials (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009), EMBASE (1980 to June 2009), and reference lists of articles.
Trials were selected if they were randomised and compared the effectiveness of laparoscopic surgery in the treatment of subfertility associated with endometriosis versus other treatment modalities or placebo.
Two studies were eligible for inclusion within the review. Both studies compared laparoscopic surgical treatment of minimal and mild endometriosis compared with diagnostic laparoscopy only. The recorded outcomes included live birth, pregnancy, fetal losses, and complications of surgery.
When combining live birth rate and ongoing pregnancy after 20 weeks, meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only. The odds ratio (OR) was 1.64 (95% confidence interval (Cl) 1.05 to 2.57) in favour of laparoscopic surgery. Meta-analysis also demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only in terms of clinical pregnancy rates, with an OR of 1.66 (95% Cl 1.09 to 2.51) favouring laparoscopic surgery. The results still need to be interpreted with caution as Marcoux 1997 reported a large positive effect of surgery whereas Gruppo Italiano reported a small negative effect. When considering fetal losses, meta-analysis did not demonstrate an effect of laparoscopic surgery when compared to diagnostic laparoscopy only. The OR was 1.33 (95% Cl 0.60 to 2.94) favouring diagnostic laparoscopy only.
The use of laparoscopic surgery in the treatment of subfertility related to minimal and mild endometriosis may improve future fertility.
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity. It is variable in both its surgical appearance and clinical manifestation often with poor correlation between the two. Surgical treatment of endometriosis aims to remove visible areas of endometriosis and restore anatomy by division of adhesions and relieve painful symptoms.
To assess the efficacy of laparoscopic surgery in the treatment of pelvic pain associated with endometriosis.
For the update in July 2009 we searched the Cochrane Menstrual Disorders and Subfertility Group's specialised register of trials (searched July 2009), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 July 2009), EMBASE (1980 July 2009), and reference lists of articles.
Randomised controlled trials were selected comparing the effectiveness of laparoscopic surgery used to treat pelvic pain associated with endometriosis, with other treatment modalities or diagnostic laparoscopy only.
Assessment of trial quality and extraction of relevant data was performed independently by two reviewers.
Five studies were included in the meta-analysis, including three full papers and two conference reports. All the randomised controlled trials with the exception of Lalchandani 2003 compared different laparoscopic surgical techniques with diagnotic laparoscopy only. Lalchandani 2003 compared laparoscopic coagulation therapy with diagnostic laparoscopy and medical treatment. Three studies (Abbott 2004; Sutton 1994; Tutunaru 2006) reported the pain scores six months post operatively. Meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only (OR of 5.72 95%Cl 3.09 to 10.60 ; 171 participants, three trials, Analysis 1.1). A single study (Tutunaru 2006) reported pain scores twelve months after the procedure. Analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy only (OR of 7.72 95%Cl 2.97 to 20.06 ; 33 participants, one trial, Analysis 1.1).
Laparoscopic surgery results in improved pain outcomes when compared to diagnostic laparoscopy alone. There were few women diagnosed with severe endometriosis included in the meta-analysis and therefore any conclusions from this meta-analysis regarding treatment of severe endometriosis should be made with caution. It is not possible to draw conclusions from the meta-analysis which specific laparoscopic surgical intervention is most effective.
[Show abstract][Hide abstract] ABSTRACT: Women who have had a child with mitochondrial DNA (mtDNA) disease need to know the risk of recurrence, but this risk is difficult to estimate because mutant and wild-type (normal) mtDNA coexist in the same person (heteroplasmy). The possibility that a single sample may not reflect the whole organism both impedes prenatal diagnosis of most mtDNA diseases, and suggests radical alternative strategies such as nuclear transfer. We used naturally occurring mtDNA variants to investigate mtDNA segregation in placenta. Using large samples of control placenta, we demonstrated that the level of polymorphic heteroplasmic mtDNA variants is very similar in mother, cord blood and placenta. However, where placental samples were very small (< 10 mg) there was clear evidence of variation in the distribution of mtDNA polymorphic variants. We present the first evidence for variation in mutant load, that is, mosaicism for mtDNA polymorphic variants in placenta. This suggests that mtDNA mutants may segregate in placenta and that a single chorionic villous sample (CVS) may be unrepresentative of the whole placenta. Duplicates may be necessary where CVS are small. However, the close correlation of mutant load in maternal, fetal blood and placental mtDNA suggests that the average load in placenta does reflect the load of mutant mtDNA in the baby. Provided that segregation of neutral and pathogenic mtDNA mutants is similar in utero, our results are generally encouraging for developing prenatal diagnosis for mtDNA diseases. Identifying mtDNA segregation in human placenta suggests studies of relevance to placental evolution and to developmental biology.
European Journal of HumanGenetics 07/2006; 14(7):816-23. · 4.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pregnancy outcome and characteristics of women who conceive following subfertility treatment remains a subject of great interest. We analyzed these variables among 199 women who delivered a registerable twin birth compared with 1773 women who delivered a naturally conceived twin birth in a population-based obstetric cohort drawn from around Oxford, England. Treatment was restricted to conceptions involving simple ovulation induction only. Treated mothers were of significantly higher social class and older, more likely to deliver girls and to be delivered by cesarean section, and significantly less likely to be smokers at the time of antenatal booking and to have delivered previous pregnancies. Pregnancy outcome was similar between the two groups for most measures, with the exception of birthweight which was lower in treated twins, though not significantly so. Overall the results are reassuring with respect to outcome in twin pregnancies following simple ovulation induction.
Twin Research and Human Genetics 05/2006; 9(2):279-84. · 1.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To report the trends in career choices for obstetrics and gynaecology among UK medical graduates.
Postal questionnaire surveys of qualifiers from all UK medical schools in nine qualification years since 1974.
All graduates from UK medical schools in 1974, 1977, 1980, 1983, 1993, 1996, 1999, 2000 and 2002.
Postal questionnaire surveys.
Career choices for obstetrics and gynaecology and factors influencing career choices for obstetrics and gynaecology.
Seventy-four percent (24,623/33,417) and 73% (20,709/28,468) of doctors responded at 1 and 3 years after qualification. Choices for obstetrics and gynaecology fell sharply during the 1990s from 4.2% of 1996 qualifiers to 2.2% of 1999 qualifiers, and rose slightly to 2.8% of 2002 qualifiers. Only 0.8% of male graduates of 2002 chose obstetrics and gynaecology compared with 4.1% of women. Forty-six percent of those who chose obstetrics and gynaecology 1 year after qualification were working in it 10 years after qualifying. Experience of the subject as a student, and the influence of a particular teacher or department, affected long-term career choices more for obstetrics and gynaecology than for other careers.
The unwillingness of young doctors to enter obstetrics and gynaecology may be attributable to concerns about workforce planning and career progression problems, rather than any lack of enthusiasm for the specialty. The number of men choosing obstetrics and gynaecology is now very small; the reasons and the future role of men in the specialty need to be debated.
BJOG An International Journal of Obstetrics & Gynaecology 04/2006; 113(3):350-6. · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are three approaches to hysterectomy for benign disease - abdominal hysterectomy (AH), vaginal hysterectomy (VH) and laparoscopic hysterectomy (LH). Laparoscopic hysterectomy has three further subdivisions - laparoscopic assisted vaginal hysterectomy (LAVH) where a vaginal hysterectomy is assisted by laparoscopic procedures that do not include uterine artery ligation, laparoscopic hysterectomy (which we will abbreviate to LH(a)) where the laparoscopic procedures include uterine artery ligation, and total laparoscopic hysterectomy (TLH) where there is no vaginal component and the vaginal vault is sutured laparoscopically.
To assess the most appropriate surgical approach to hysterectomy.
We searched the Cochrane Menstrual Disorders & Subfertility Group's Specialised Register of controlled trials (searched 23 March 2004), CENTRAL (The Cochrane Library Issue 1, 2004), MEDLINE (1966 to Mar 2004), EMBASE (1985 to Mar 2004), Biological Abstracts (1968 to Mar 2004), the National Research Register and relevant citation lists.
Only randomised trials comparing one surgical approach to hysterectomy with another were included.
Twenty-seven trials that included 3643 participants were included. Independent selection of trials and data extraction were employed following Cochrane guidelines.
The benefits of VH versus AH were shorter duration of hospital stay (WMD 1.0 day, 95%CI 0.7 to 1.2 days), speedier return to normal activities (WMD 9.5 days, 95%CI 6.4 to 12.6 days), fewer unspecified infections or febrile episodes (OR 0.42, 95%CI 0.21 to 0.83). The benefits of LH versus AH were lower intraoperative bloodloss (WMD 45.3 mls, 95%CI 17.9 to 72.7 mls) and a smaller drop in haemoglobin level (WMD 0.55g/L, 95%CI 0.28 to 0.82g/L), shorter duration of hospital stay (WMD 2.0 days, 95%CI 1.9 to 2.2 days), speedier return to normal activities (WMD 13.6 days, 95%CI 11.8 to 15.4 days), fewer wound or abdominal wall infections (OR 0.32, 95%CI 0.12 to 0.85), fewer unspecified infections or febrile episodes (OR 0.65, 95%CI 0.49 to 0.87), at the cost of longer operating time (WMD 10.6 minutes, 95%CI 7.4 to 13.8 minutes) and more urinary tract (bladder or ureter) injuries (OR 2.61, 95%CI 1.22 to 5.60). There was no evidence of benefits of LH versus VH and the operating time was increased (WMD 41.5 minutes, 95%CI 33.7 to 49.4 minutes). There was no evidence of benefits of LH(a) versus LAVH and the operating time was increased for LH(a) (WMD 25.3 minutes, 95%CI 10.0 to 40.6 minutes). There was statistical heterogeneity in many of the outcome measures when randomised trials were pooled for meta-analysis. No other statistically significant differences were found. However, for some important outcomes, the analyses were underpowered to detect important differences, or they were simply not reported in trials. Data were notably absent for many important long-term outcome measures.
Significantly improved outcomes suggest VH should be performed in preference to AH where possible. Where VH is not possible, LH may avoid the need for AH, however the length of the surgery increases as the extent of the surgery performed laparoscopically increases, particularly when the uterine arteries are divided laparoscopically and laparoscopic approaches require greater surgical expertise. The surgical approach to hysterectomy should be decided by a woman in discussion with her surgeon in light of the relative benefits and hazards. Further research is required with full reporting of all relevant outcomes, particularly important long-term outcomes, in large RCTs, to minimise the possibility of reporting bias. Further research is also required to define the role of the newer approaches to hysterectomy such as TLH.
[Show abstract][Hide abstract] ABSTRACT: It has been reported that preimplantation human embryos secrete HLA-G, and the levels may be predictive of their ability to implant. However, it is not known which of the membrane-bound (HLA-G 1-4) and soluble (HLA-G 5-6) alternatively spliced forms are present, nor the developmental stage at which they appear. Therefore, we have investigated HLA-G mRNA isoform expression on single embryos at the two-, four-, six-, and eight-cell, morula, and blastocyst stages. The percentage of embryos expressing each HLA-G isoform mRNA increased with developmental stage, but contrary to expectation, HLA-G5 mRNA was not detected in single two- to eight-cell embryos and was only expressed by 20% of morulae and blastocysts. Similarly, soluble HLA-G6 mRNA was not detected until the blastocyst stage and then in only one-third of embryos. In contrast, labeling with MEM G/9 Ab (specific for HLA-G1 and -G5) was observed in 15 of 20 two- to eight-cell embryos and 5 of 5 blastocysts. This disparity between mRNA and protein may be due to HLA-G protein remaining from maternal oocyte stores produced before embryonic genome activation and brings into question the measurement of soluble HLA-G for clinical evaluation of embryo quality. Although HLA-G is expressed in the preimplantation embryo, later it is primarily expressed in the invasive trophoblast of the placenta rather than the fetus. Therefore, we have investigated whether down-regulation of HLA-G first occurs in the inner cell mass (precursor fetal cells) of the blastocyst and, in support of this concept, have shown the absence HLA-G1 and -G5 protein and mRNA.
The Journal of Immunology 01/2006; 175(12):8379-85. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.
The American Journal of Human Genetics 10/2005; 77(3):365-76. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the most appropriate surgical method of hysterectomy (abdominal, vaginal, or laparoscopic) for women with benign disease.
Systematic review and meta-analysis.
Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase, and Biological Abstracts.
Only randomised controlled trials were selected; participants had to have benign gynaecological disease; interventions had to comprise at least one hysterectomy method compared with another; and trials had to report primary outcomes (time taken to return to normal activities, intraoperative visceral injury, and major long term complications) or secondary outcomes (operating time, other immediate complications of surgery, short term complications, and duration of hospital stay).
27 trials (total of 3643 participants) were included. Return to normal activities was quicker after vaginal than after abdominal hysterectomy (weighted mean difference 9.5 (95% confidence interval 6.4 to 12.6) days) and after laparoscopic than after abdominal hysterectomy (difference 13.6 (11.8 to 15.4) days), but was not significantly different for laparoscopic versus vaginal hysterectomy (difference -1.1 (-4.2 to 2.1) days). There were more urinary tract injuries with laparoscopic than with abdominal hysterectomy (odds ratio 2.61 (95% confidence interval 1.22 to 5.60)), but no other intraoperative visceral injuries showed a significant difference between surgical approaches. Data were notably absent for many important long term patient outcome measures, where the analyses were underpowered to detect important differences, or they were simply not reported in trials.
Significantly speedier return to normal activities and other improved secondary outcomes (shorter duration of hospital stay and fewer unspecified infections or febrile episodes) suggest that vaginal hysterectomy is preferable to abdominal hysterectomy where possible. Where vaginal hysterectomy is not possible, laparoscopic hysterectomy is preferable to abdominal hysterectomy, although it brings a higher chance of bladder or ureter injury.
[Show abstract][Hide abstract] ABSTRACT: IL-11 signaling is critical for decidualization of the endometrial stroma in early pregnancy in the mouse. In this study, we investigate the function of IL-11 signaling in cAMP-induced decidualization of human endometrial stromal cells. We show that treatment of endometrial stromal cells with 8-bromo-cAMP (8-Br-cAMP) results in an increase in the levels of secreted IL-11, whereas levels of cell surface IL-11 receptor alpha are similar with or without 8-Br-cAMP treatment. The production of IL-11 correlates with the production of molecular markers of decidualization, prolactin and IGF-binding protein-1. The expression of these markers is inhibited when IL-11 signaling is specifically blocked in decidualizing endometrial stromal cells by the IL-11 antagonist W147A. We demonstrate that 8-Br-cAMP-induced endometrial stromal cells derived from patients with primary infertility produce lower levels of prolactin, IGF-binding protein-1, and IL-11 than cells derived from fertile women. Our results suggest that IL-11 expression is critically important during decidualization in the human endometrium, and that aberrant regulation of endometrial IL-11 production may be associated with some types of infertility.
[Show abstract][Hide abstract] ABSTRACT: Heparin-binding epidermal growth factor (HB-EGF) has pleiotropic biological functions in many tissues, including those of the female reproductive tract. It facilitates embryo development and mediates implantation and is thought to have a function in endometrial receptivity and maturation. The mature HB-EGF molecule manifests its activity as either a soluble factor (sol-HB-EGF) or a transmembrane precursor (tm-HB-EGF) and can bind two receptors, EGFR and ErbB4/HER4. In this study, we identify factors that modulate expression of HB-EGF, EGFR, and ErbB4 in endometrial stromal cells in vitro. We demonstrate that levels of sol- and tm-HB-EGF, EGFR, and ErbB4 are increased by cAMP, a potent inducer of decidualization of the endometrial stroma. We also show that production of sol- and tm-HB-EGF is differentially modulated by TNF alpha and TGF beta. Our data suggest that HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF alpha- and TGF beta-induced apoptosis of endometrial stromal cells.
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is a relatively common condition in women of reproductive age and is associated with considerable morbidity. Despite an extensive literature describing its multiple clinical manifestations, their management, and many aspects of the biology of endometriotic lesions, the pathophysiological mechanisms involved remain poorly understood. A genetic component in endometriosis is now recognized, and several groups have taken up the challenge of using genetic techniques to identify the aberrant molecular and cellular mechanisms in endometriosis with the intention of providing much-needed insights that might, in turn, lead to new therapies. The techniques that have been applied include expression profiling, tumor genetic studies, functional candidate gene studies, and linkage studies that can adopt a hypothesis-free approach. This review describes the current status of these studies and explores the prospects for new therapies.
Annual Review of Medicine 02/2005; 56:345-56. · 14.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endometriosis is inherited as a complex trait, which means that multiple susceptibility genes interact with each other and the environment to produce the phenotype. Previous studies have implicated p53, a tumor suppressor gene, as a factor in the development of the disease. In a Japanese population, we investigated the frequency of the p53 polymorphism in women affected with endometriosis.
We compared the distribution of the p53 codon 72 polymorphism in endometriosis cases (n = 111) and population controls consisting of female neonates (n = 180) by using polymerase chain reaction restriction fragment-length polymorphism analysis in a Japanese population.
The frequencies of the three p53 genotypes, Arginine (Arg)/Arg, Arg/Proline (Pro), and Pro/Pro in controls were 39.4%, 41.7%, and 18.9 %, respectively. The crude genotype frequencies in the endometriosis cases were similar to those of the controls (35.2%, 48.6%, and 16.2%, respectively). Using the Arg/Arg genotype as the reference, the odds ratios of the Arg/Pro and Pro/Pro genotypes were 1.30 (95% confidence interval [CI] 0.72-1.86, P =.33) and 0.96 (95% CI 0.47-1.94, P =.91), respectively. Thus, there were no significant differences in the frequency of the p53 codon 72 polymorphism between endometriosis cases and controls in this population. The endometriosis cases with severe disease only were also evaluated, but no significant difference was observed in the frequency of the polymorphism between this subgroup and the controls.
Our findings suggest that the p53 codon 72 polymorphism is unlikely to be associated with endometriosis in Japanese women.
Journal of the Society for Gynecologic Investigation 06/2004; 11(4):232-6. · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The decline in circulating oestrogen around the time of the menopause often induces unacceptable symptoms that affect the health and well being of women. Hormone replacement therapy (both unopposed oestrogen and oestrogen and progestogen combinations) is an effective treatment for these symptoms. In women with an intact uterus, unopposed oestrogen may induce endometrial stimulation and increase the risk of endometrial hyperplasia and carcinoma. The addition of progestogen reduces this risk but may cause unacceptable symptoms, bleeding and spotting which can affect adherence to therapy.
The objective of this review is to assess which hormone replacement therapy regimens provide effective protection against the development of endometrial hyperplasia and/or carcinoma with a low rate of abnormal vaginal bleeding.
We searched the Cochrane Menstrual Disorders and Subfertility Group trials register (searched January 2003), The Cochrane Library (Issue 2, 2003), MEDLINE (1966 to January 2003), EMBASE (1980 to January 2003), Current Contents (1993 to January 2003), Biological Abstracts (1969 to 2002), Social Sciences Index (1980 to January 2003), PsycINFO (1972 to February 2003) and CINAHL (1982 to January 2003). The search strategy was developed by the Cochrane Menstrual Disorder and Subfertility Group. Attempts were also made to identify trials from citation lists of review articles and drug companies were contacted for unpublished data. In most cases, the corresponding author of each included trial was contacted for additional information.
The inclusion criteria were randomised comparisons of unopposed oestrogen therapy, combined continuous oestrogen-progestogen therapy and sequential oestrogen-progestogen therapy with each other and placebo administered over a minimum treatment period of six months. Trials had to assess which regimen was the most protective against the development of endometrial hyperplasia/carcinoma and/or caused the lowest rate of irregular bleeding.
Sixty RCTs were identified. Of these 23 were excluded and seven remain awaiting assessment. The reviewers assessed the thirty included studies for quality, extracted the data independently and odds ratios for dichotomous outcomes were estimated. Outcomes analysed included frequency of endometrial hyperplasia or carcinoma, frequency of irregular bleeding and unscheduled biopsies or dilation and curettage, and adherence to therapy.
Unopposed moderate or high dose oestrogen therapy when compared to placebo was associated with a significant increase in rates of endometrial hyperplasia with increasing rates at longer duration of treatment and follow up. Odds ratios ranged from (1 RCT; OR 5.4, 95% CI 1.4 to 20.9) for 6 months of treatment to (4 RCTs; OR 9.6, 95% CI 5.9 to 15.5) for 24 months treatment and (1 RCT; OR 15.0, 95% CI 9.3 to 27.5) for 36 months of treatment with moderate dose oestrogen (in the PEPI trial, 62% of those who took moderate dose oestrogen had some form of hyperplasia at 36 months compared to 2% of those who took placebo). Irregular bleeding and non adherence to treatment were also significantly more likely under these unopposed oestrogen regimens that increased bleeding with higher dose therapy. Although not statistically significant, there was a 3% incidence (2 RCTs) of hyperplasia in women who took low dose oestrogen compared to no incidence of hyperplasia in the placebo group. The addition of progestogens, either in continuous combined or sequential regimens, helped to reduce the risk of endometrial hyperplasia and improved adherence to therapy. At longer duration of treatment, continuous therapy was more effective than sequential therapy in reducing the risk of endometrial hyperplasia. There was evidence of a higher incidence of hyperplasia under long cycle sequential therapy (progestogen given every three months) compared to monthly sequential therapy (progestogen given every month). No increase in endometrial cancer was seen in any of t in any of the treatment groups during the duration (maximum of six years) of these trials. During the first year of therapy irregular bleeding and spotting was more likely in continuous combined therapy than sequential therapy. However, during the second year of therapy bleeding and spotting was more likely under sequential regimens.
There is strong and consistent evidence in this review that unopposed oestrogen therapy, at moderate and high doses, is associated with increased rates of endometrial hyperplasia, irregular bleeding and consequent non adherence to therapy. The addition of oral progestogens administered either sequentially or continuously is associated with reduced rates of hyperplasia and improved adherence to therapy. Irregular bleeding is less likely under sequential than continuous therapy during the first year of therapy but there is a suggestion that continuous therapy over long duration is more protective than sequential therapy in the prevention of endometrial hyperplasia. Hyperplasia is more likely when progestogen is given every three months in a sequential regimen compared to a monthly progestogen sequential regimen.