Maltreatment during childhood: a risk factor for the development of endometriosis?

STUDY QUESTION: Is maltreatment during childhood (MC), e.g. sexual abuse, physical abuse, emotional abuse and neglect, associated with diagnosis of endometriosis? SUMMARY ANSWER: Childhood sexual abuse, emotional abuse/neglect and inconsistency experiences were associated with the diagnosis of endometriosis while no such association was found for physical abuse/neglect and other forms of maltreatment. WHAT IS KNOWN ALREADY: Symptoms of endometriosis such as chronic pelvic pain, fatigue and depression, are correlated with MC, as are immune reactions linked to endometriosis. These factors support a case for a potential role of MC in the development of endometriosis. STUDY DESIGN, SIZE, DURATION: The study was designed as a multicentre retrospective case-control study. Women with a diagnosis of endometriosis were matched to control women from the same clinic/doctor's office with regard to age (±3 years) and ethnic background. A total of 421 matched pairs were included in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with endometriosis and control women were recruited in university hospitals, district hospitals, and doctors' offices in Germany, Switzerland and Austria. A German-language version of the Childhood Trauma Questionnaire (CTQ) was used to evaluate MC. Diagnosis of endometriosis was confirmed histologically and classified according to ASRM criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Women with endometriosis reported significantly more often than control women a history of sexual abuse (20%/14%, P = 0.0197), emotional abuse (44%/28%, P < 0.0001), emotional neglect (50%/42%, P = 0.0123) and inconsistency experiences (53%/41%, P = 0.0007). No statistically significant differences could be demonstrated for physical abuse/neglect (31%/26%, P = 0.1738). Combinations of different abuse/neglect experiences were described significantly more often in women with endometriosis. Frequencies of other MC, i.e. violence against the mother (8%/7%, P = 0.8222), drug abuse in the family (5%/3%, P = 0.0943), mentally handicapped family members (1%/1%, P = 0.7271), suicidal intentions in the family (6%/4%, P = 0.2879) and family members in prison (1%/1%, P = 0.1597) were not statistically different in women with endometriosis and control women. LIMITATIONS, REASONS FOR CAUTION: Some control women might present asymptomatic endometriosis, which would lead to underestimation of our findings. The exclusion of pregnant women may have biased the results. Statistical power for sub-analyses of physical abuse/neglect and sexual abuse was limited. WIDER IMPLICATIONS OF THE FINDINGS: A link to MC needs to be considered in women with endometriosis. As there are effective strategies to avoid long-term consequences of MC, healthcare professionals should inquire about such experiences in order to be able to provide treatment for the consequences as early as possible. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Endo_QoL NCT02511626.

Comparison of quartz vials with polypropylene vials for rapid cryopreservation of human ovarian tissue.

BACKGROUND: Because higher survival of follicles during the freezing/thawing procedure improves the quality of cryopreserved tissue reimplanted after oncological therapies, defining an optimal method for human ovarian tissue cryopreservation remains a major issue in this field. One option to improve the cryopreservation procedure is to use better materials, i.e., vials with better conductivity. The aim of this study was to compare polypropylene (PP) with quartz vials. Between September 2012 and January 2013, eight patients were recruited. The ovarian cortex was cut into 3 slices, assigned randomly to a fresh and a cryopreserved group in PP (method B) or quartz vials (method C). Histological and immunohistochemical (IHC) analysis were used. For IHC three antibodies were analyzed: Ki67 (proliferation index), Bcl2 (anti apoptotic index) and Hsp70 (stress index). RESULTS: The majority of GCs showed positive staining for Bcl2 in both cryopreservation device, with higher expression in group C than in group B. Oocytes and their nuclei showed intense positive staining for ki67 in both methods B and C, and also a patch positive stromal cells staining for Ki67. Expression of hsp70 was not increased after cryopreservation. CONCLUSIONS: Cryopreservation using quartz vials led to larger numbers of good follicles while maintaining consistent preservation for stromal cells and vessels.

A multi-centre phase 3 study comparing efficacy and safety of Bemfola(®) versus Gonal-f(®) in women undergoing ovarian stimulation for IVF.

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20-38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: -1.34, 1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

Recommendations for raloxifene use in daily clinical practice in the Swiss setting.

BACKGROUND/AIM: Raloxifene is the first selective estrogen receptor modulator that has been approved for the treatment and prevention of osteoporosis in postmenopausal women in Europe and in the US. Although raloxifene reduces the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer, it is approved in that indication in the US but not in the EU. The aim was to characterize the clinical profiles of postmenopausal women expected to benefit most from therapy with raloxifene based on published scientific evidence to date. METHODS: Key individual patient characteristics relevant to the prescription of raloxifene in daily practice were defined by a board of Swiss experts in the fields of menopause and metabolic bone diseases and linked to published scientific evidence. Consensus was reached about translating these insights into daily practice. RESULTS: Through estrogen agonistic effects on bone, raloxifene reduces biochemical markers of bone turnover to premenopausal levels, increases bone mineral density (BMD) at the lumbar spine, proximal femur, and total body, and reduces vertebral fracture risk in women with osteopenia or osteoporosis with and without prevalent vertebral fracture. Through estrogen antagonistic effects on breast tissue, raloxifene reduces the risk of invasive estrogen-receptor positive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. Finally, raloxifene increases the incidence of hot flushes, the risk of venous thromboembolic events, and the risk of fatal stroke in postmenopausal women at increased risk for coronary heart disease. Postmenopausal women in whom the use of raloxifene is considered can be categorized in a 2 × 2 matrix reflecting their bone status (osteopenic or osteoporotic based on their BMD T-score by dual energy X-ray absorptiometry) and their breast cancer risk (low or high based on the modified Gail model). Women at high risk of breast cancer should be considered for treatment with raloxifene. CONCLUSION: Postmenopausal women between 50 and 70 years of age without climacteric symptoms with either osteopenia or osteoporosis should be evaluated with regard to their breast cancer risk and considered for treatment with raloxifene within the framework of its contraindications and precautions.

[Sexual medicine cases of treatment--developments 1980 - 1990 - 2004]. / Sexualmedizinische Behandlungsfälle - Entwicklungen 1980 - 1990 - 2004.

Sexual dysfunctions can adversely affect men's and women's satisfaction with life over a prolonged period. Besides sexual medicine services in primary medical care, in Switzerland there exist specialized consultation services at University Hospitals. The assessment of the case histories of three years (1980, 1990, and 2004) of the Sexual Medicine Consultation Service at Zurich University Hospital provided the following results: the most common disorders are lack/loss of libido in women and erectile dysfunction in men. Treatment options for sexual disorders have become more differentiated in recent years. The collaboration between the doctors making the referral and the sexual medicine specialists improved markedly between 1980 and 2004. After a diagnostic assessment and a primary treatment in the specialized consultation service, many patients are referred back to the referring doctors for further treatment. Basic and further training in sexual medicine ought to be intensified and improved.

[New developments in reproductive medicine]. / Neue Entwicklungen in der Fortpflanzungsmedizin.

Several developments in the field of reproductive medicine intend to improve the efficiency of the treatment and to reduce the number of unwanted side effects. These advancements are among others the production of long-acting FSH, polar body biopsy and the identification of factors, which can optimize the implantation potential of the endometrium. Cryopreservation of ovarian tissue enables the maintenance of fertility in tumor patients.

Effects of the progestagen-only contraceptive implant Implanon on transforming growth factor beta1 and endothelin-1.

Progestagen-only contraceptives are often prescribed to women with an increased cardiovascular risk, despite the fact that only few data are available on the effect of these contraceptives on circulating biomarkers of inflammation and endothelial function. In our prospective case-control study, we aimed to investigate the influence of the low-dose etonogestrel-releasing contraceptive implant Implanon on endothelin-1 and cytokine transforming growth factor beta (TGF-beta1), both factors involved in the early phases of atherogenesis. We also were interested in searching for an interrelation between changes in these two parameters and changes in female hormones and plasma lipids. Cases (n=20) were women using Implanon for contraception, and controls (n=20) were females not using hormonal contraception. Baseline blood samples were taken during the early follicular phase of cycle 1 in both groups. A second sample was taken 12 weeks after Implanon insertion or, for controls, in the early follicular phase of cycle 4. In both groups no significant change in endothelin-1 or TGF-beta1 was observed. In Implanon users, cholesterol, high-density lipoprotein, low-density lipoprotein, sex hormone-binding globulin, and testosterone decreased significantly. No correlations were found between endothelin-1 or TGF-beta1 and the investigated parameters. The results suggest that Implanon does not exert a clinically relevant negative effect on endothelin-1 or TGF-beta.

Partial and complete expulsion of the Multiload 375 IUD and the levonorgestrel-releasing IUD after correct insertion.

OBJECTIVE: The contraceptive efficacy of intrauterine devices (IUD) is thought to relate to the position of the IUD in the uterine cavity. Several trials examined the number of copper IUD expulsions, but none evaluated the partial and complete expulsion rate of the levonorgestrel-releasing device (LNG-IUD). STUDY DESIGN: This retrospective cohort study compares the dislocation rate of the Multiload 375 IUD (ML 375) and the LNG-IUD in 214 women (107 subjects with each IUD). Transvaginal ultrasound was used to monitor the IUD position immediately after insertion, after 6 weeks, and later on at intervals of 6 months. The observation period included 3631 cycles. RESULTS: We detected a significantly lower number of dislocations in LNG-IUD users. Previous expulsion was associated with a significantly higher risk for a re-expulsion in both IUD groups. Hypermenorrhea was not associated with an increased dislocation rate in LNG-IUD users. CONCLUSION: Expulsions are less likely to occur with the LNG-IUD, which might contribute to its contraceptive efficacy.

[Psychosomatic aspects of endometriosis--current state of scientific knowledge and clinical experience]. / Psychosomatische Aspekte der Endometriose--aktueller Stand der wissenschaftlichen Kenntnisse und der klinischen Erfahrungen.

Current therapeutic options allow successful treatment in only part of the women presenting with endometriosis. Pain, fatigue/exhaustion, intensive and repeated therapies as well as a concentration on the disease lead to a variety of consequences concerning education/ profession, body perception, self-esteem, partnership/social contacts, sexuality and psychic well-being. Difficulties in becoming pregnant represent a further central problem in dealing with endometriosis. Therefore, biopsychosocial aspects should be integrated into current somatically oriented models of medical support.

Family stability during childhood and the risk to develop hypertensive diseases in pregnancy.

BACKGROUND: Parental care giving, divorce and death are associated with physical health as an adult. AIM: To investigate whether the structure of the nuclear family during childhood shows any correlation with the development of hypertensive diseases in pregnancy as an adult. STUDY DESIGN: Self-administered questionnaires were sent to 2600 women with hypertensive diseases in pregnancy and to 1484 controls. SUBJECTS: After confirmation of the diagnosis data from 842 patients and 623 control women were evaluated. OUTCOME MEASURES: Type, number and involvement of different caregivers, parental separation, parental death. RESULTS: In both groups parental separation and parental death were found equally often. In all age groups during childhood fathers were involved significantly less often in care giving when women with hypertensive disorders in pregnancy were compared to control women (1st-3rd year 23.4%/17%, <0.0001; 4th-10th year 25.7%/19.3%, <0.0001; 11th-18th year 30.1%/23.9%, <0.0001). The total number of caregivers involved was significantly higher in patients. CONCLUSIONS: The quality of parental care giving, i.e. the involvement of fathers and the total number of caregivers correlate with the risk to develop HDP. Further research is needed to specify underlying mechanisms and the relevant factors of the parent-child relationship.

Absence of Yq microdeletions in infertile men.

Microdeletions of the long arm of the Y chromosome (Yq) were described in men with idiopathic azoo- or oligozoospermia and seem to cause impairment of spermatogenesis. Deletion frequencies differ considerably among selected infertile men. The aim of this study was to investigate the prevalence of Yq microdeletions in patients with idiopathic infertility. Men with azoospermia or oligozoospermia resulting from endocrine or obstructive causes or with a constitutional cytogenetic anomaly were excluded. Ninety-seven patients presenting at infertility centers in Leipzig and Zurich were included in the study. Sixty-four (66%) of them were severely oligozoospermic (sperm concentrations < 5 x 10(6)/mL) and 33 (36%) were azoospermic. A sequence-tagged site (STS) PCR strategy was applied for the microdeletion screening. Thirteen STS markers spanning the whole euchromatic region of Yq were used. No Y-chromosomal microdeletion could be detected in these 97 infertile men. This result suggests a much lower Yq deletion frequency than previously thought, even among strictly selected patients with idiopathic azoo- or oligozoospermia.

Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism.

Estradiol inhibits endothelin-1 synthesis, an effect that may contribute to the cardiovascular protective effects of estradiol. Recent findings that estradiol inhibits neointima formation in mice lacking estrogen receptors suggests that the cardiovascular protective effects of estradiol may be mediated by means of an estrogen receptor-independent mechanism. Because 2-hydroxyestradiol and 2-methoxyestradiol, metabolites of estradiol with little/no affinity for estrogen receptors, are more potent than estradiol in inhibiting vascular smooth muscle cell growth, we investigated whether these metabolites also inhibit endothelin-1 synthesis by means of an receptor-independent mechanism. Treatment of porcine coronary artery endothelial cells for 4 to 24 hours with 0.001 to 1 micromol/L of estradiol, 2-hydroxyestradiol, or 2-methoxyestradiol concentration-dependently inhibited basal as well as serum-induced (2.5%), TNFalpha-induced (10 ng/mL), angiotensin II-induced (100 nmol/L), and thrombin-induced (4 U/mL) endothelin-1 synthesis. Estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol also inhibited serum-induced mitogen-activated protein kinase activity. As compared with estradiol, its metabolites were more potent in inhibiting endothelin-1 secretion and mitogen activated protein kinase activity. The inhibitory effects of 2-hydroxyestradiol and 2-methoxyestradiol on endothelin-1 release and mitogen-activated protein kinase activity were not blocked by ICI182780 (50 micromol/L), an estrogen receptor antagonist. Our findings indicate that the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol potently inhibit endothelin-1 synthesis by means of an estrogen receptor-independent mechanism. This effect of estradiol metabolites may be mediated by inhibition of mitogen activated protein kinase activity and may contribute to the cardioprotective effects of estradiol.

Increased incidence of numerical chromosome abnormalities in spermatozoa injected into human oocytes by ICSI.

The potential risk of transmitting chromosomally abnormal spermatozoa from infertile males into oocytes through intracytoplasmic sperm injection (ICSI) has prompted us to investigate the male pronuclei of tripronuclear zygotes (3PN) obtained after ICSI. To specify the type of anomalies, we used triple colour fluorescent in-situ hybridization (FISH) with three specific probes for chromosomes X, Y and 18. From a total of 163 paternal complements of ICSI-3PN zygotes, 90 (55.2%) had Y-chromosome signals. Eighty-three of these were normal, four had the disomy XY and three were diploid. In the remaining 73 ICSI-3PN zygotes without Y-chromosome signals, the origin of paternal pronuclei was extrapolated through chromosome constitution of the first polar body. Five anomalies were found in this group of zygotes, giving a total rate of numerical chromosome aberrations for fertilizing spermatozoa of 7.4%. In contrast to ICSI, only two disomies (1.5%) were found in the control group of IVF-3PN zygotes. Compared with the incidence of chromosome anomalies between paternal-derived pronuclei of ICSI- and IVF-3PN zygotes, the difference was statistically significant (P < 0.025). This study provides the first direct evidence of a higher incidence of numerical chromosome anomalies in sperm-fertilized human oocytes after ICSI.

[Climacteric syndrome]. / Das klimakterische Syndrom.

The most frequent symptoms of the climacteric syndrome are hot flushes. Although usually they disappear after a few years, hot flushes persist for five or more years in a quarter of the affected women. Aetiology and pathomechanism are not clear. Apart from oestrogen deficiency other diseases should be evaluated as potential causes of hot flushes such as psychosomatic disorders, hyperthyroidism and a neoplasm. The treatment of the first choice is an oestrogen replacement therapy. By assaying a single serum sample for oestradiol an oestrogen replacement therapy can be monitored reliably only in the case of transdermal application.

Cellular and biochemical mechanisms by which environmental oestrogens influence reproductive function.

The biology and physiology of the male as well as female reproductive system is hormonally regulated. Abnormalities in the dynamics of hormone production, metabolism and elimination, as well as their binding to certain target tissues, has been associated with pathophysiological conditions of the reproductive system. Although oestrogens are known to be one of the major hormone groups in regulating the reproductive function and the fertilization process, the cellular and biochemical mechanism or mechanism(s) via which oestrogens induce their effects are still not fully defined. Moreover, in a modern environment we are also exposed to a wide battery of environmental agents which are structurally similar to oestrogens, and termed 'environmental oestrogens'. Because environmental oestrogens have been shown to mimic some of the effects of oestradiol, it has been postulated that these exogenous chemicals may influence or interfere with the oestrogen-dependent reproductive processes, and may be associated with beneficial as well as deleterious effects on the reproductive system. In this regard, two classes of environmental oestrogens have been widely studied, i.e. phyto-oestrogens (plant-derived dietary oestrogens) and xeno-oestrogens (industrial chemicals, including polychlorinated biphenyls, DDT, TCDD, dioxins, etc.). The main focus of this review is to provide an overview on the cellular and biochemical mechanism(s) by which xeno-oestrogens and phyto-oestrogens influence the oestrogen-dependent reproductive functions and induce their deleterious or protective effects on the reproductive system.

Vascular effects of environmental oestrogens: implications for reproductive and vascular health.

Environmental oestrogens are defined as xenobiotics structurally resembling oestrogen, and are divided into two broad categories, xeno-oestrogens and phyto-oestrogens. Environmental oestrogens may contribute importantly to the increased incidence of reproductive disorders in the modern environment. Although the mechanisms by which environmental oestrogens induce their deleterious effects on the reproductive system remain poorly defined, it is likely that the vascular effects of these compounds play a critical role. In this regard, oestradiol strongly regulates both angiogenesis and vascular remodelling by influencing the growth and function of vascular endothelial cells (EC) and smooth muscle cells (SMC). Since blood vessels, by undergoing angiogenesis, vascular regression and vascular remodelling, actively participate in the normal functioning of reproductive organs, environmental oestrogens-by mimicking or antagonizing the vascular effects of oestradiol-may induce abnormalities in vascular function and structure leading to reproductive disorders such as pre-eclampsia, endometriosis, impaired follicular development, inefficient implantation, impotence and infertility. The purpose of the present review is to summarize the evidence regarding the vascular effects of xeno-oestrogens and phyto-oestrogens and to discuss the implications for these effects on the reproductive system.

Gonadotrophin administration can benefit ovarian tissue grafted to the body wall: implications for human ovarian grafting.

Ovarian grafting provides a strategy for clinical infertility treatment and is starting to be used in conjunction with ovarian tissue storage for patients at risk of early ovarian failure. As patients are starting to return for their frozen stored tissue we need to ascertain how to maximise follicle survival when this tissue is grafted back to the patient. For research purposes ovarian tissue is commonly grafted to the kidney capsule as the rich capillary bed at this site favours rapid graft revascularization. This is however not an ideal site for natural conceptions or for the harvest of mature oocytes for in vitro fertilization. While oocytes would be relatively easy to recover from grafts on the abdominal wall or subcutaneous tissue graft revascularization at these sites is slower and evidence indicates that fewer follicles survive. As gonadotropins can upregulate angiogenic growth factors in the ovary this study was designed to test whether the administration of exogenous gonadotropins would increase the number of surviving follicles in grafts placed at less vascularised sites. We showed that exogenous gonadotrophins, given to either the donor or the recipient, could increase the number of developing follicles but the magnitude of this effect was influenced by the timing of the injections relative to the time of grafting.

The effect of the menstrual cycle and of ethinylestradiol on nitric oxide, endothelin-1 and homocysteine plasma levels.

The use of the estrogen ethinylestradiol is associated with an increased cardiovascular risk. It is not known whether this might be caused by an influence of ethinylestradiol on endothelium-derived factors or on the cardiovascular risk factor homocysteine. Our aim was to evaluate whether a short-term treatment with ethinylestradiol results in changes of nitric oxide (NO), endothelin-1 and homocysteine. Participants were ten healthy women with regular menstrual cycles. NO, homocysteine, endothelin-1, estradiol and progesterone were measured during one cycle and before and after treatment with ethinylestradiol at 50 microg/day. Homocysteine and NO did not change significantly during the menstrual cycle or after treatment. However, endothelin-1 levels decreased during the cycle (from 3.89 ng/l to 2.93 ng/l p < 0.05) and after ethinylestradiol (from 2.94 ng/l to 2.26 ng/l p<0.03). Analysis of the pretreatment data showed a positive correlation between homocysteine and NO and between NO and endothelin-1. Treatment with ethinylestradiol caused a shift in the balance between NO and endothelin-1 in the direction of vasodilatation. This finding is one factor concerning the effects of ethinylestradiol on the vascular system but does not explain the cardiovascular risk of this substance.

Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity.

Some estrogenic compounds modify vascular smooth muscle cell (SMC) biology; however, whether such effects are mediated in part by estrogen receptors is unknown. The purpose of this study was to evaluate whether the actions of clinically used estrogens on human aortic SMC biology are mediated by estrogen receptors. We examined the effects of various clinically used estrogens in the presence and absence of ICI 182,780, an estrogen receptor antagonist, on cultured human aortic SMC DNA synthesis ([(3)H]thymidine incorporation), cellular proliferation (cell counting), cell migration (modified Boyden chamber), collagen synthesis ([(3)H]proline incorporation), and mitogen-activated protein kinase activity. FCS-induced DNA synthesis, cell proliferation, collagen synthesis, platelet-derived growth factor-induced SMC migration, and mitogen-activated protein kinase activity were significantly inhibited by physiological (10(-9) mol/L) concentrations of 17beta-estradiol and low concentrations (10(-8) to 10(-7) mol/L) of 17beta-estradiol, estradiol valerate, estradiol cypionate, and estradiol benzoate but not by estrone, estriol, 17alpha-estradiol, or estrone sulfate. The inhibitory effects of 17beta-estradiol and other inhibitory estrogens were completely reversed by 100 micromol/L ICI 182,780, and the rank-order potency of various estrogens to inhibit SMC biology matched their rank-order affinity for estrogen receptors. The inhibitory effects of estrogens on SMC biology are in part receptor-mediated. Because the cardioprotective effects of hormone replacement therapy are most likely mediated by modification of SMC biology, whether hormone replacement therapy protects a given postmenopausal woman against cardiovascular disease will depend partially on the affinity of the estrogen for estrogen receptors in vascular SMCs.