Velja Mijatovic

Essure hysteroscopic tubal occlusion device for the treatment of hydrosalpinx prior to in vitro fertilization-embryo transfer in patients with a contraindication for laparoscopy

OBJECTIVE To investigate the success rate of proximal tubal occlusion with Essure devices in subfertile women with hydrosalpinges, and to observe the results of subsequent treatment with IVF. DESIGN Prospective, single-arm, clinical study. SETTING University hospital and teaching hospital. PATIENT(S) Ten women with uni- or bilateral hydrosalpinges prior to IVF. In all patients laparoscopy was felt to be contraindicated. INTERVENTION(S) Hysteroscopic placement of Essure devices in an office setting. MAIN OUTCOME MEASURE(S) Placement rate, successful proximal tubal occlusion, and pregnancy rate after IVF. RESULT(S) All patients had successful placement of the Essure devices without any complications. Proximal tubal occlusion was confirmed by hysterosalpingography in 9 out of 10 patients. A 40% ongoing pregnancy rate was achieved with 20% life births after one IVF cycle and/or frozen embryo transfer. CONCLUSION(S) Proximal occlusion of hydrosalpinges with Essure devices before IVF is a successful treatment for patients with a contraindication for salpingectomy.

Adenomyosis has no adverse effects on IVF/ICSI outcomes in women with endometriosis treated with long-term pituitary down-regulation before IVF/ICSI☆

OBJECTIVES To establish the effect of adenomyosis on IVF/ICSI outcomes in infertile patients with endometriosis who were pretreated with long-term (>/=3 months) GnRH-agonist prior to IVF/ICSI. STUDY DESIGN Retrospective study in 74 infertile patients with surgically proven endometriosis who were treated with IVF/ICSI between January 2002 and March 2007. The diagnosis of adenomyosis was based on transvaginal ultrasound criteria. All patients were pretreated with long-term (>or=3 months) GnRH-agonist prior to IVF/ICSI. RESULTS 90.4% of the patients were diagnosed with endometriosis rASRM stages III-IV. Adenomyosis was demonstrated in 27% of them and was predominantly located in the posterior wall of the uterus. The following IVF/ICSI outcomes were found: a mean duration of GnRH-agonist use prior to IVF/ICSI of 5.35 months (3-26); a mean dosage of FSH used of 208IU (75-450); the mean number of oocytes retrieved was 8.73 (1-30); the mean number of embryos obtained was 3.86 (0-16); the mean number of embryos transferred was 1.6; a mean fertilization rate of 43.6%; a mean implantation rate of 26.3%; a mean miscarriage rate of 24.3%; and a clinical pregnancy rate (fetal heart activity on ultrasound beyond 12 weeks of gestation) of 31.7%. No significant differences were found for any of the IVF/ICSI outcomes between women with and without adenomyosis. CONCLUSIONS Adenomyosis had no adverse effects on IVF/ICSI outcomes in infertile women with proven endometriosis who were pretreated with long-term GnRH-agonist.

Familial Mediterranean fever and its implications for fertility and pregnancy

Familial Mediterranean fever (FMF) is a recessively inherited disease of episodic fever in combination with severe abdominal pain, pleurisy, arthritis or erysipelas-like skin rashes. The disease is mainly prevalent in Sephardic Jews, Armenians, Turks and Arabs. The gene responsible for FMF was cloned in 1997. The gene expresses a protein called pyrin which is believed to play a role in the downregulation of mediators of inflammation. Several mutations have been identified of which the homozygous form of the M694V mutation is associated with a more severe expression of FMF. Prophylactic administration of colchicine is effective in relieving most patients from their attacks and preventing the development of amyloidosis, which usually leads to end-stage renal disease. Unfortunately, there is little awareness of the disease in gynaecological practice although a FMF full blown episode may mimic an acute abdominal calamity suggesting several possible gynaecological diagnoses. FMF is also associated with subfertility. In females, infertility was mainly related to oligomenorrhea although the causes remain unclear. In male FMF patients, progression of the disease may induce testicular impairment, consequently affecting spermatogenesis. Some controversy exists as to the adverse effects of colchicine on sperm production and function although the impression is that the occurrence of sperm pathology in FMF patients, using the recommended dosage of colchicine, is very low. In pregnant FMF patients, an increased occurrence of miscarriage has been found. However, the mechanisms involved remain unclear. Although colchicine is a mitotic inhibitor and transplacental crossing of colchicine has been demonstrated, no increased risk of foetal abnormalities in colchicine-treated pregnant FMF patients has been found. Therefore, amniocentesis should not be done for reassurance alone.

Emerging Selective Estrogen Receptor Modulators Special Focus on Effects on Coronary Heart Disease in Postmenopausal Women

Menopause, regardless of age at onset, is associated with a marked increase in coronary heart disease (CHD) risk. On the basis of epidemiological studies that demonstrated mainly positive effects of postmenopausal hormone therapy on CHD as well as on risk markers of CHD, it has been suggested that CHD could be prevented in postmenopausal women with long-term hormone therapy. However, since the publications of the Heart and Estrogen/progestin Replacement Study and the Women’s Health Initiative trial, prescription of hormone therapy for the prevention of CHD has become controversial.Major efforts have been made to identify alternatives for hormone therapy. Compounds suggested have included selective estrogen receptor modulators (SERMs), which represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This pharmacological profile may offer the opportunity to dissociate favourable estrogenic effects on the bone and cardiovascular system from unfavourable stimulatory effects on the breast and endometrium. Two SERMs presently on the market are tamoxifen and raloxifene. The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. These trials found fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo.Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures, is safe for the endometrium and holds high promise for the prevention of breast cancer. The effect of raloxifene on CHD is still uncertain. On the basis of the MORE (Multiple Outcomes of Raloxifene Evaluation) trial, raloxifene may offer some protection to women with CHD or to those who are at high risk of CHD. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway.Next-generation SERMs taken into clinical development include idoxifene, droloxifene, ospemifene, arzoxifene, acolbifene/EM-800, levormeloxifene, lasofoxifene, bazedoxifene and HMR 3339. The aim is to find a compound with the ideal profile, that is, alleviation of climacteric symptoms and prevention of osteoporotic fractures, but without an adverse effect on the breast and endometrium, and no negative effect or even a beneficial effect on the cardiovascular system and the brain. Currently, limited data are available with regard to these next-generation SERMs and CHD. Nevertheless, some of these novel agents provide arguments for continuing the search for an ideal SERM.

Magnetic resonance imaging in the evaluation of (deep infiltrating) endometriosis: The value of diffusion‐weighted imaging

To assess the value of magnetic resonance (MR) diffusion‐weighted imaging (DWI) in the evaluation of deep infiltrating endometriosis (DIE).

Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.

Objective To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. Design In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 &mgr;g transdermal 17&bgr;-estradiol (tE2, n = 33), 1 mg oral 17&bgr;-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 &mgr;g gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. Results In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, −4.7%; oE2, −6.9%; oE2 + G, −10.5%) and LDL cholesterol (tE2, −5.8%; oE2, −12.6%; oE2 + G, −13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (−6.6%) and the oE2 + G group (−8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. Conclusions Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.

Essure® hydrosalpinx occlusion prior to IVF-ET as an alternative to laparoscopic salpingectomy

OBJECTIVE To investigate the success rate of proximal tubal occlusion with Essure(®) devices in subfertile women with unilateral or bilateral hydrosalpinx and to observe the results of subsequent treatment with IVF-ET and/or frozen embryo transfer. STUDY DESIGN Prospective, single-arm, clinical study in 20 women with unilateral or bilateral hydrosalpinges (all visible on transvaginal ultrasound) due to undergo IVF-ET and/or frozen embryo transfer. In all patients, laparoscopy was considered to be contraindicated due to extensive pelvic adhesions. RESULT(S) In all patients the Essure(®) devices were placed in an ambulant setting without any complications. Proximal tubal occlusion was confirmed by hysterosalpingography in 19 out of 20 patients (95%) and in 26 of 27 treated tubes (96%). After 45 embryo transfer procedures in 19 patients, 18 pregnancies with 12 live births, 6 miscarriages and 1 immature delivery (probably related to cervical insufficiency leading to chorioamnionitis and subsequent rupture of the membranes) were observed. CONCLUSION(S) Essure(®) devices are effective in inducing proximal tubal occlusion in subfertile patients with hydrosalpinges. After artificial reproductive treatments a cumulative live birth rate per patient of 63% and a cumulative live birth rate per transfer of 27% were achieved. The latter was related to the large proportion of patients with severe endometriosis.

Homocysteine in postmenopausal women and the importance of hormone replacement therapy.

Abstract Homocysteine (Hcy) has been shown to damage the vascular endothelial cells, contributing to atherothrombosis. The increase in plasma Hcy levels with natural menopause suggests a close relationship between Hcy metabolism and estrogen status and proposes one of the mechanisms through which menopause unfavorably affects cardiovascular disease risk in women. In addition to the prevention of osteoporosis, hormone replacement therapy (HRT) lowers Hcy levels in postmenopausal women. The first report by van der Mooren et al., demonstrated in an uncontrolled study a significant reduction (11%) in fasting serum Hcy level after 6 months of treatment with sequentially combined estradiol-dydrogesterone therapy in 21 healthy postmenopausal women. This effect was particularly evident in women with initially elevated baseline serum Hcy concentrations. Similar results were found in other studies in which women were treated with various transdermal as well as oral HRT regimens, although two studies could not confirm these findings. All these studies were uncontrolled, and three of them consisted of a relatively small number of participants. Therefore, they remained inconclusive. Three randomized controlled trials on HRT and Hcy were published to date, confirming that postmenopausal HRT reduces circulating levels of Hcy. Current and recent HRT use is associated with a slight increased risk of breast cancer. As a result of this, research has centered on finding compounds that can prevent the consequences of estrogen deficiency, without the potential risk of HRT. Raloxifene, referred to as a Selective Estrogen Receptor Modulator (SERM), has the potential as a viable alternative to HRT. Recently, two randomized controlled trials demonstrated that raloxifene lowers plasma Hcy levels in postmenopausal women, similar to the reduction obtained with HRT. Little is known about the mechanisms underlying the HRT-associated lowering of plasma Hcy. Proposed mechanisms relate to an increase in kidney methionine synthase activity or may be related to the transamination of methionine. We conclude that HRT decreases plasma Hcy levels in postmenopausal women and that the strongest reductions can be achieved in women with the highest concentrations.

Hormone replacement therapy, selective estrogen receptor modulators, and tissue-specific compounds: cardiovascular effects and clinical implications.

In industrialized countries, coronary heart disease (CHD) is not only the leading cause of death in women but of disability as well. Menopause, regardless of age at onset, is associated with a marked increase in CHD risk. Based on epidemiologic studies demonstrating mainly positive biologic effects of hormone replacement therapy (HRT) on CHD risk factors and outcomes, earlier recommendations decreed that most, if not all, postmenopausal women should be treated with long-term HRT. Recent randomized controlled trials with clinical CHD endpoints have shown that previously held dicta may not be accurate.Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene are alternatives to HRT. SERMs represent a growing class of compounds that act as either estrogen receptor agonists or antagonists in a tissue-selective manner. This pharmacologic profile may offer the opportunity to dissociate favorable cardiovascular effects of estrogen from unfavorable stimulatory effects on the breast and endometrium.The only data available regarding the effects of tamoxifen on cardiovascular events in postmenopausal women are from breast cancer trials. They showed fewer fatal myocardial events in women randomly assigned to tamoxifen compared with women assigned to placebo. Raloxifene is a so-called second-generation SERM. It seems clear that raloxifene increases bone mineral density, has no effect on the endometrium, and holds high promise for the prevention of breast cancer. The effect of raloxifene on cardiovascular disease is uncertain. On the basis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene may offer some protection to women with cardiovascular disease or to those who are at high risk. Proof that raloxifene reduces the risk of CHD requires a clinical trial with hard clinical endpoints. Such a study is currently underway.Clinical trials have demonstrated that the synthetic 19-nortestosterone derivative tibolone reduces climacteric complaints and prevent osteoporosis without causing menstrual bleeding. Tibolone lowers lipoprotein(a), fibrinogen, and plasminogen activator inhibitor-1 levels and improves glucose tolerance, insulin sensitivity, and endothelial function; however, it also lowers high-density lipoprotein cholesterol by >20%. The long-term impact of tibolone on the risk of CHD is not known and needs to be studied.

Efficacy and safety of intrauterine insemination in patients with moderate-to-severe endometriosis

Performing intrauterine insemination (IUI) in moderate-to-severe endometriosis patients is not implemented in international guidelines, as only limited data exist on treatment efficacy and safety. This retrospective study examined the efficacy and safety of two IUI treatment strategies performed between January 2007 and July 2012 in moderate-to-severe endometriosis patients. Eight (40.0%) versus seven (15.6%) ongoing pregnancies were accomplished in patients undergoing IUI with ovarian stimulation (n=20, 61 cycles) versus IUI without ovarian stimulation in the first three cycles followed by IUI with ovarian stimulation (IUI with natural/ovarian stimulation; n=45, 184 cycles). Preceding long-term pituitary down-regulation tended to result in a higher ongoing pregnancy rate (adjusted HR 1.8) and a higher chance of endometriosis recurrence (adjusted HR 2.3). Eight (40.0%) versus 16 (35.6%) recurrences of endometriosis complaints were reported in patients receiving IUI with ovarian stimulation versus IUI with natural/ovarian stimulation. IUI might be a valuable treatment in moderate-to-severe endometriosis patients and IUI with ovarian stimulation should be offered over IUI with natural/ovarian stimulation. Preceding long-term pituitary down-regulation might positively influence the ongoing pregnancy rate and can be considered. Whether this treatment strategy can be structurally offered prior to IVF must be investigated in a randomized controlled trial.