Continuous Oral Contraceptives Research Articles

Influence of menstrual cycle and hormonal contraceptive use on MS symptom fluctuations: A pilot study.

In clinical practice, females with MS often report menstrually-related symptom fluctuations. Hypothetically, use of oral contraceptives (OCs) could reduce these fluctuations, particularly continuous OCs (11+ weeks of consistent exogenous hormones followed by 1 week placebo). To prospectively capture (1) whether neurologic and generalized symptoms vary with menstrual cycle phase and (2) whether type of contraception impacts symptom fluctuations. In this two-center pilot study, females with MS and a regular menstrual cycle prospectively tracked their menstrual cycles and completed symptom surveys for up to 6 months. Participants were categorized as 1) users of oral contraceptives, either a) cyclic or b) continuous, or 2) endogenously cycling, either c) hormonal intrauterine device (IUD) users or d) "none users" (e.g. no hormonal contraception; included condoms, copper IUD, tubal ligation, "fertility awareness methods"). There was no correction for multiple analyses. Altogether, 47/70 participants (67%) provided >4 weeks of data and were included in the analyses. Mean (SD) age was 35.0 (0.9) years, median (IQR) EDSS was 1.5 (1-2) and mean (SD) SymptoMScreen score was 10.4 (9.6). For endogenously cycling patients (IUD and none users), fatigue (MFIS) was lower in the perimenstrual period than in the luteal period (p<0.05). For continuous OC users, variability in symptoms was lower than for endogenously cycling females (MFIS: p<0.01; Daily Hassles, from Uplift & Hassles Survey: p<0.05) or cyclic OC users (MFIS: p<0.001). In this pilot study, symptom severity did not definitively fluctuate in relationship to the menstrual cycle in endogenously cycling participants. However, fatigue and daily hassles were less variable for participants using continuous OC than for cyclic OC users or no-OC users. Future confirmatory studies are warranted to further examine whether contraceptive choice can be leveraged to manage symptom fluctuation in cycling females with MS. Such studies could enroll larger cohorts over fewer cycles or employ incentivization and hormonal measurements to enhance participant retention and statistical power.

Autoimmune progesterone dermatitis: a retrospective case series.

Background:Autoimmune progesterone dermatitis (APD) is a rare hypersensitivity disorder characterized by recurring dermatologic manifestations during the luteal phase of the menstrual cycle in women. Well-defined clinical and diagnostic criteria, outcomes measurements, and standard treatments are lacking.Methods:We performed a single-institution retrospective review of adult patients (older than 20 years at the time of diagnosis) with APD.Results:Fourteen patients were included with mean age of clinical onset of 34.3 ± 7.7 (range 24-54) years. There was a delay of 3.9 ± 5.5 (range 0.4-20) years between the onset of disease symptoms and diagnosis. The onset of APD was after exposure to exogenous progesterone in 9 of 14 patients. Progesterone skin test was performed in 9 patients and 6 were positive. Patients frequently presented with urticaria (9/14, 64.3%) and dermatitis (4/14, 28.6%). Continuous combined oral contraceptives (4/14, 28.6%), gonadotropin-releasing hormone agonist (3/14, 21.4%), and hysterectomy with bilateral salpingo-oophorectomy (2/14, 14.3%) were the most common attempted treatments with reliable outcomes.Conclusions:APD is a rare disorder which lacks universal diagnostic measures and criteria, contributing to a significant delay in diagnosis. Large-scale multicenter studies are needed to develop accurate tests, establish diagnostic criteria, and define treatment outcomes.

Oral contraceptive use and anterior cruciate ligament injury: comparison of active comparator new user cohort and case-control study designs

BackgroundThis study further investigates a protective association between oral contraceptive (OC) use and anterior cruciate ligament (ACL) injury noted in prior case-control studies.MethodsActive comparator new user cohort analysis of women aged 13–45 years in the United States from the IBM MarketScan Commercial Claims and Encounters database who newly-initiated low-dose OCs (exposed) or underwent intrauterine device (IUD) insertion (comparison group) from 2000 to 2014. Women were followed for ACL injury starting 90 days after OC initiation or IUD insertion until OC or IUD discontinuation or end of continuous enrollment. Adjusted hazard ratios (adjHR) and 95% confidence intervals (CI) were estimated controlling for age. Secondary analysis replicated previously-published case-control studies assessing “ever” versus “never” OC use over 1- and 5-year periods among women who underwent ACL reconstruction compared to age-matched controls.ResultsIn the cohort analysis, 2,370,286 women initiated OCs and 621,798 underwent IUD insertion. There were 3571 (0.15%) ACL injuries during an average 370.6 days of continuous OC use and 1620 (0.26%) during an average 590.5 days of IUD use. No difference in risk of ACL injury was observed between OC initiators and IUD users (adjHR = 0.95; 95%CI 0.89, 1.01). The case-control analysis replicated the slight protective association observed in prior studies over a 5-year period (OR = 0.90; 95%CI 0.85, 0.94).ConclusionsThis cohort study suggests no association between OC use and ACL injury, while the case-control study suggested bias from uncontrolled confounding and selection factors may have influenced previous findings that suggested a protective association between OC use and ACL injury.

Long-term hormonal treatment reduces repetitive surgery for endometriosis recurrence

Research questionHow effective is medical hormonal treatment in preventing endometriosis recurrence and in improving women's clinical symptoms and quality of life? DesignThis observational cross-sectional study evaluated the effects of hormonal medical treatment (progestins, gonadotrophin-releasing hormone analogues or continuous oral contraceptives) on endometriosis recurrence, current clinical symptoms and quality of life in three groups of patients: Group A (n = 34), no hormonal treatment either before or after the first endometriosis surgery; Group B (n = 76), on hormonal treatment after the first endometriosis surgery; and Group C (n = 75), on hormonal treatment both before and after the first endometriosis surgery. ResultsGroup C patients were characterized by a lower rate of endometriosis reoperation (P = 0.011) and a lower rate of dysmenorrhoea (P = 0.006). Women who experienced repetitive endometriosis surgery showed worse physical (P = 0.004) and mental (P = 0.012) status than those who received a single surgery, independent of the treatment. ConclusionHormonal treatments represent a valid cornerstone of endometriosis management and may be useful as an alternative to surgery, but also before surgery, to plan better, and after surgery in order to reduce the risk of recurrence. Medical counselling is very helpful in choosing the correct and individualized endometriosis treatment. In fact, the gold standard for modern endometriosis management is the individualized approach and surgery should be considered, depending on the clinical situation and a patient's symptoms.

SUN-916 Novel Germline p.Gly42Arg MEN1 Missense Mutation in a Family Harboring Very Aggressive Pancreatic Tumor, Hyperparathyroidism and Pituitary Tumor

Background.Pancreatic neuroendocrine tumors ocurs in 30-80% of patients with MEN-1, and may be non-functioning and hormone secreting tumors. Non-functioning GEP-NETs are increasingly recognised due to advanced imaging modalities such as endoscopic ultrasound thus became the most common type in MEN1 patients. Several mutations MENIN gene were described, although patients with missense mutations are considered as low-impact mutation carriers.Case report.Index case, female, 47 years old, menarche at age of 16yo, amenorrhea until 23yo, when started continuous oral contraceptives. At age of 45 presented dizziness, paresthesia, cramps, had the diagnosis of Hyperparathyroidism related to multinodular parathyroid hyperplasia (Calcium 14mg/dL, PTH 117 pg/mL) and macroprolactinoma (prolactin 235 ng/mL; pituitary tumor 1.2 X 1.0 cm). All siblings and her mother were recruited and one brother, aged 45 years confirmed the diagnosis of hyperparathyroidism and nephrocalcinosis. Their mother, aged 77 years old, presented abdominal pain, and had the diagnosis of aggressivepancreatic tumor compressing bile duct causing intra and extra-pancreatic dilation, associated with metastatic lymph nodes. She was sunmitted to total pancreato-gastrectomy with esophagus jejunum anastomosis. Genetic screening:MEN1genetic screening for mutations was performed in all patients. In these probands, MLPA analysis was performed to detect large deletions of the MEN1gene, using SALSA MLPA probemix kit P017-D1 according to the manufacturer’s instructions (MRC-Holland, Amsterdam, The Netherlands).DNA was extracted from EDTA-Whole blood using MagNA Pure 24 (Roche). Sequencing libraries were qualified/quantified using TapeStation4200 (Agilent). Test method included coding regions ±10bp flanking intronic sequences of 3921 genes enriched using Kappa HyperPlus Library Preparation Kit (Roche) and SeqCap EZ inherited disease panel (Roche) and sequenced (2x75-bp Mid Output V2 Reagent) using NextSeq-500 (Illumina) (estimated mean coverage-100X). Read alignment, variant calling, variant filtration and annotation were performed with Varstation. SNVs and small indels (20bp) with total-read-depth,10X and variant-read-frequency more than20% found on AIP, APC, CDC73, CDKN1B, DICER1, FH, MAX, MEN1, MET, NF1, PRKAR1A, PTEN, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, VHL, WRN genes were analyzed.A missense mutation in exon 2, MEN1:c.124G.C:p.(GLY42Arg) was detected. Discussion and conclusion:MEN1-associated GEP-NETs seem to have a low proliferation rate and long survival has been reported, they should be of particular attention, since they are still the principal cause of death in MEN1 patients.Early screening and diagnosis are crucial for MEN-1 phenotypes.

Patterns in the Management of Endometriosis Among Physicians: A Cross-Sectional Survey [28A

INTRODUCTION: Management of endometriosis is complex and varies among providers. This study investigates patterns in the management of endometriosis among Obstetrics and Gynecology physicians in the United States. METHODS: The Institutional Review Board reviewed and approved this study. A national online survey was sent to 5000 members of the American College of Obstetrics and Gynecology. It included 22 questions designed to assess the medical, surgical, and pain management of endometriosis. Variations in management were assessed using Fisher exact test and Mann-Whitney test. RESULTS: The adjusted response rate was 24.5%. The most common initial treatment for pelvic pain and suspected endometriosis was continuous combined oral contraceptives (COCs) (58%). When medical management fails, 52% of respondents opt for surgical management; 45% of respondents treat with excision while 42% treat with cautery ablation. Most indicated they offer postoperative hormone suppression, including continuous COCs (45%) or gonadotropin-releasing hormone agonists with add-back therapy (27%). The majority prescribe nonsteroidal anti-inflammatory drugs to treat endometriosis-related pain while a minority opt for alternative treatments such as opioids, acupuncture, and psychological support. 82% of physicians believe there is a need for women with endometriosis to have psychosocial care; however, only 15% routinely refer patients for psychological counseling. Importantly, 72% of respondents indicated they do not feel adequately trained to provide care for psychosocial aspects of endometriosis. CONCLUSION: The majority of responding providers are practicing evidence-based care for the treatment of endometriosis. Although most physicians recognize the need for a multidisciplinary approach to the treatment of endometriosis-related pain, only a minority recommend alternative treatments.

Comparison of MS inflammatory activity in women using continuous versus cyclic combined oral contraceptives

BackgroundMany women with multiple sclerosis (MS) report fluctuating symptoms across their menstrual cycle. Oral contraceptives (OCs) alter hormonal levels across the menstrual cycle. While cyclic OCs administer hormones for 21 days, followed by a week of placebo, continuous OCs can administer continuous doses of hormones for up to 3 months. Previous studies have suggested that OC use is associated with lower MS-related inflammation. We hypothesized that due to reduced hormonal fluctuations, women with MS might experience less inflammatory activity (clinical relapses+MRI) on continuous OCs than on cyclic OCs. MethodsWe performed a retrospective analysis of prospectively collected data. For women with MS aged 18–50 seen at the UCSF Center for MS and Neuroinflammation, we extracted data on OC use from the Electronic Medical Records (EMR). All variables were confirmed using manual clinical chart review. We identified 19 women with relapsing forms of MS on continuous OCs and matched them (2:1 when possible) to women on cyclic OCs for OC formulation, age, MS duration and DMT type. Inflammatory activity in the two groups was then compared using log-rank tests (time to new relapse, new T2-weighted lesion formation, and gadolinium-enhancing lesion formation) and t-tests (annualized relapse rate). We also performed subgroup analyses in women with at least 1 year (N = 28) and 2 years (N = 21) of clinical observation. A power calculation was performed. ResultsThere was no difference in time to relapse (p = 0.50) between continuous and cycling OC users. However, continuous OC users showed a statistical trend to longer time to T2 lesion formation (p = 0.09) and longer time to contrast-enhancing lesion formation (p = 0.05). In patients with at least 1 year of observation, there was a significant difference in time to T2 lesion formation (p = 0.03) and time to contrast-enhancing lesion formation (p = 0.02). ConclusionIn this exploratory study, women on continuous OCs showed a trend towards less inflammatory activity on MRI relative to women on cyclic OCs. This difference was not reflected in relapse rates. We estimate that 342 patients would be required for an adequately powered cohort study to evaluate such an effect. Our findings provide reassurance that for women using continuous OCs to alleviate menstrual fluctuations in symptoms, there is not an increase in MS-related inflammatory activity.

Time to full effect, following treatment with combined oral contraceptives (cyclic versus continuous administration) in patients with endometriosis after laparoscopic surgery: a prospective cohort study

The risk of recurrence after surgery is a major problem in women who are suffering from endometriosis. The prescription oral contraceptives (OCs) in the treatment of endometriosis-related pain, in women who do not desire fertility, is still controversial. The aim of this prospective cohort study is to evaluate the time until the reduction in the mean intensity of dysmenorrhoea and deep dyspareunia takes effect, for patients who use combined OCs in the accepted cyclic manner, versus in the continuous fashion as after the laparoscopic excision of endometriosis. A total of 28 patients diagnosed with endometriosis who underwent surgical treatment were offered at least a 12 months course of oral contraceptives. The intensity of both symptoms was reduced at the end of observational period in both groups. The use of continuous OCs (11 patients) was associated with a more pronounced reduction in the mean intensity of dyspareunia and dysmenorrhoea at 9 (p = 0.004) and 6 (p = 0.003) months respectively as compared to the cyclic group (17 patients).

Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.

Endometriosis is known to have an impact on fertility and it is common for women affected by endometriosis to require fertility treatments, including in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), to improve the chance of pregnancy. It has been postulated that long-term gonadotrophin-releasing hormone (GnRH) agonist therapy prior to IVF or ICSI can improve pregnancy outcomes. This systematic review supersedes the previous Cochrane Review on this topic (Sallam 2006). To determine the effectiveness and safety of long-term gonadotrophin-releasing hormone (GnRH) agonist therapy (minimum 3 months) versus no pretreatment or other pretreatment modalities, such as long-term continuous combined oral contraception (COC) or surgical therapy of endometrioma, before standard in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with endometriosis. We searched the following electronic databases from their inception to 8 January 2019: Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched trial registries to identify unpublished and ongoing trials. We also searched DARE (Database of Abstracts of Reviews of Effects), Web of Knowledge, OpenGrey, Latin American and Caribbean Health Science Information Database (LILACS), PubMed, Google and reference lists from relevant papers for any other relevant trials. Randomised controlled trials (RCTs) involving women with surgically diagnosed endometriosis that compared use of any type of GnRH agonist for at least three months before an IVF/ICSI protocol to no pretreatment or other pretreatment modalities, specifically use of long-term continuous COC (minimum of 6 weeks) or surgical excision of endometrioma within six months prior to standard IVF/ICSI. The primary outcomes were live birth rate and complication rate per woman randomised. Two independent review authors assessed studies against the inclusion criteria, extracted data and assessed risk of bias. A third review author was consulted, if required. We contacted the study authors, as required. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs) and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups and presented with 95% CIs. We studied heterogeneity of the studies via the I2 statistic. We assessed the quality of evidence using GRADE criteria. We included eight parallel-design RCTs, involving a total of 640 participants. We did not assess any of the studies as being at low risk of bias across all domains, with the main limitation being lack of blinding. Using GRADE methodology, the quality of the evidence ranged from very low to low quality. Long-term GnRH agonist therapy versus no pretreatment We are uncertain whether long-term GnRH agonist therapy affects the live birth rate (RR 0.48, 95% CI 0.26 to 0.87; 1 RCT, n = 147; I2 not calculable; very low-quality evidence) or the overall complication rate (Peto OR 1.23, 95% CI 0.37; to 4.14; 3 RCTs, n = 318; I2 = 73%; very low-quality evidence) compared to standard IVF/ICSI. Further, we are uncertain whether this intervention affects the clinical pregnancy rate (RR 1.13, 95% CI 0.91 to 1.41; 6 RCTs, n = 552, I2 = 66%; very low-quality evidence), multiple pregnancy rate (Peto OR 0.14, 95% CI 0.03 to 0.56; 2 RCTs, n = 208, I2 = 0%; very low-quality evidence), miscarriage rate (Peto OR 0.45, 95% CI 0.10 to 2.00; 2 RCTs, n = 208; I2 = 0%; very low-quality evidence), mean number of oocytes (MD 0.72, 95% CI 0.06 to 1.38; 4 RCTs, n = 385; I2 = 81%; very low-quality evidence) or mean number of embryos (MD -0.76, 95% CI -1.33 to -0.19; 2 RCTs, n = 267; I2 = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.

Clinical, hormonal and metabolic parameters in women with PCOS with different combined oral contraceptives (containing chlormadinone acetate versus drospirenone)

IntroductionPolycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5–10% of women of reproductive age. It is characterized by chronic anovulation leading to menstrual disorders, and increased infertility. The syndrome can also manifest as hirsutism and acne.Aim of the studyThe aim of the study was to compare, over a duration of 6 months, the effects of drospirenone (DRSP) versus chlormadinone acetate (CMA) containing oral contraceptives (OCs) on clinical, hormonal, and metabolic parameters in 120 PCOS women.Materials and methods120 women with the diagnosis of PCOS according to the Rotterdam 2003 criteria were recruited to the study. All patients were divided to two treatment groups of OCs, containing: 3 mg DRSP/30 mcg EE (ethinylestradiol) (60 patients) and 2 mg CMA/30 mcg EE (60 patients). Clinical parameters such as hirsutismus and acne were evaluated. Metabolic parameters such as serum insulin, glucose concentration, homeostatic model assessment of insulin resistance, body mass index, systolic and diastolic blood pressures were also measured. Among hormonal parameters, serum estradiol, luteinizing hormone, follicle-stimulating hormone, prolactin, testosterone, dehydroepiandrosterone sulfate, thyroid-stimulating hormone, and free thyroxine were measured.ResultsThe use of both DRSP- or CMA-containing OCs provided similar positive therapeutic effects with regard to clinical, metabolic, and hormonal parameters. Among clinical parameters, like hirsutismus, after 6 months of continuous OC treatment, a statistically significant improvement was observed in both groups: DRSP (p < 0.0001) and CMA OC treatment (p < 0.0001). In addition, significant improvement was showed according to acne lesions both after DRSP (p < 0.0001) and CMA treatments (p < 0.0001). Among glucose, insulin levels and HOMA-IR, there were statistically significant higher levels in both groups after DRSP (p < 0.0001, p < 0.0001, p < 0.05) and CMA OC treatment (p < 0.02, p < 0.0001, p < 0.0001). Hormonal parameters such as LH, FSH, prolactin, testosterone and DHEA-S were statistically significant lower in both groups after DRSP (p < 0.0001, p < 0.0001, p < 0.01, p < 0,002, and p < 0.0001) and CMA OC treatment (p < 0.0001, p < 0.0001, p < 0.04, p < 0.002, and p < 0.0001).ConclusionsFurther research, however, is needed not only to define optimal duration, and to clarify the effects of treatment on long-term metabolic outcomes, but also to explore different treatment options and possible combined therapies.

Deep Infiltrating Endometriosis: Using Preoperative Radiology for Surgical Planning

A 42-year-old woman presented with symptoms of intermittent bowel obstruction. Her history was significant for a robotically assisted excision of endometriosis and distal ileum resection with side-to-side anastomosis for treatment of endometriosis 4 years prior. At the time of her previous procedure, imaging suggested sigmoid endometriosis; however, she was asymptomatic, without any obstructive symptoms, and thus the lesion was not excised. Subsequently, she was treated with a 6-month course of leuprolide acetate followed by continuous oral contraceptives.

MON-233 Effect of Weight Loss and Hormonal Suppression Alone and in Combination on Bioactive Gut and Ovarian Peptide Hormones in Women with Polycystic Ovary Syndrome

BACKGROUND: Serum peptide biomarkers are frequently abnormal in women with PCOS reflecting underlying reproductive and metabolic dysfunction. The effects of treatment on these biomarkers is poorly described. METHODS: We performed a secondary analysis on obese women with PCOS who had participated in a RCT(JCEM, PMID: 26401593) where they were randomized into a 16 wk intervention to either continuous oral contraceptives(OCP, EE 20 mcg/NETA 1 mg, N= 34), an intensive life style intervention with oral weight loss drugs(WL, either orlistat or sibutramine, N=31), or the combination of the two(COMB, N=29) with OGTT and DXA body composition determination. We hypothesized that the OCP treatment group would experience primarily a treatment related alteration in ovarian biomarkers (Follistatin(FS), Activin, Inhibin A and B), whereas the weight loss group would experience a treatment related change in gut hormones [IGF-1, IGFBP-2 and Oxyntomodulin(OXM)]. Hormones were measured using Ansh Labs assays at baseline and 16 wks. General linear models with correlated errors were used for within and between group comparisons. With the exception of Follistatin, IGF-1 and Inhibin B, hormonal data were log transformed due to non-normal distributions. RESULTS: Activin A and the Inhibins were suppressed significantly by OCP with no effect of WL alone. FS nearly doubled from baseline with OCP alone[mean difference(MD) = 3.3 ng/mL, 95% CI, 2.7 -3.9 ng/mL] or in COMB(MD=2.9 ng/mL, 95%CI, 2.3 -3.6 ng/mL), both significant compared with WL alone (both P < 0.001, where WL itself had no significant change at end vs baseline). By far the most profound and unexpected suppression occurred with OXM, where on OCP alone(median change from baseline= -75.4 pg/mL, P< .001) and COMB (median change from baseline= -21.9 pg/mL, P < .001) with no effect of WL alone. OCP significantly suppressed IGF-1 levels from baseline(MD=-44 pg/mL, 95% CI, -80 to-8 pg/mL) and WL significantly increased it(MD=42 pg/mL, 95% CI, 4 -80 pg/mL) leading to a significant between group difference(P=0.001) with COMB showing no within or between group change. This was paralleled by significant OCP suppression in IGFBP-2 levels from baseline(P=003) also noted in the COMB group(P =.03). There was a significant between group difference in IGFBP-2 on OCP and COMB vs WL alone. CONCLUSION: Bioactive peptides in obese women with PCOS are significantly modulated by common treatments, though not necessarily as expected. The novel and unexpected profound suppression of OXM by OCP could lead to increased weight gain through decreased OXM-mediated anorexia and energy expenditure (though mean weight in the OCP group was unchanged over the 16 weeks). Increased IGF-1 action with WL, despite weight loss and improved AUC glucose levels on OGTT, may be due to the significant tissue remodeling(less fat, increased lean/bone mass noted on follow-up DXA scan) with our lifestyle regimen.

Comparison Of Continuous vs. Cyclic Oral Contraceptives in Women with Multiple Sclerosis (P4.2-099)

Comparison Of Continuous vs. Cyclic Oral Contraceptives in Women with Multiple Sclerosis (P4.2-099)

Continuous oral contraceptives versus long-term pituitary desensitization prior to IVF/ICSI in moderate to severe endometriosis: study protocol of a non-inferiority randomized controlled trial.

STUDY QUESTIONSThe primary objective is to investigate if continuous use of oral contraceptives is non-inferior compared to long-term pituitary desensitization with a GnRH agonist prior to IVF/ICSI in patients with moderate to severe endometriosis with regard to treatment efficacy. Secondary objectives concern treatment safety and cost-effectiveness.WHAT IS KNOWN ALREADYLong-term pituitary desensitization with a GnRH agonist for 3–6 months prior to IVF/ICSI improves clinical pregnancy rates in women suffering from endometriosis. However, discussion about this treatment strategy exists because of its uncomfortable side effects. Alternatively, IVF/ICSI pre-treatment with continuously administered oral contraceptives may offer fewer side-effects and lower (in)direct costs, as well as encouraging IVF outcomes in women with endometriosis. To date, these two different IVF/ICSI pre-treatment strategies in women with endometriosis have not been directly compared.STUDY DESIGN, SIZE, DURATIONAn open-label, parallel two-arm randomized controlled multicenter trial is planned, including patients with moderate to severe endometriosis. To demonstrate an absolute difference of 13% (delta of 10% with non-inferiority margin of 3%) with a power of 80% 137 patients per group are sufficient. Taking into account a withdrawal of patients of 10% and a cancelation rate of embryo transfer after ovarian pick up of 10% (for instance due to fertilization failure), the sample size calculation is rounded off to 165 patients per group; 330 patients in total will be included. After informed consent, eligible patients will be randomly allocated to the intervention or reference group by using web based block randomization stratified per centre. Study inclusion is expected to be complete in 3–5 years.PARTICIPANTS/MATERIALS, SETTING, METHODSThe research population consists of patients with moderate to severe endometriosis (ASRM III/IV) who are scheduled for their first, second or third IVF/ICSI treatment attempt. Women aged over 41 years, younger than 18 years, with a known contraindication for the use of oral contraceptives and/or GnRH agonists or with severe male factor infertility will be excluded from participation. After informed consent patients are allocated to the intervention group (one-phase oral contraceptive continuously during three subsequent months) or the reference group (three Leuprorelin 3.75 mg i.m./s.c. depot injections during three subsequent months). Tibolon 2.5 mg can be given daily as add-back therapy in the reference group. After 3 months of pre-treatment the IVF/ICSI stimulation phase will be started. The primary outcome is live birth rate after fresh embryo transfer. Secondary outcomes are cumulative live birth rate after one IVF/ICSI treatment cycle (including fresh and frozen embryo transfers up to 15 months after randomization), ongoing pregnancy rate and time to pregnancy. In addition, treatment outcome parameters, adverse events, side-effects during the first 3 months, complications, recurrence of endometriosis (complaints), quality of life, patient preferences, safety and costs effectiveness will be reported. Measurements will be performed at baseline and at 3, 6, 9, 12 and 15 months after randomization.STUDY FUNDING/COMPETING INTEREST(s)All authors have no conflict of interest related to this manuscript. The department of reproductive medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck and Ferring not related to the submitted work.TRIAL REGISTRATION NUMBERThe trial is registered as the COPIE trial (Continuous use of Oral contraceptives as an alternative for long-term Pituitary desensitization with a GnRH agonist prior to IVF/ICSI in Endometriosis patients) in the Dutch Trial Register (Ref. No. NTR6357, http://www.trialregister.nl).TRIAL REGISTRATION DATE16 March 2017.DATE OF FIRST PATIENT’S ENROLMENTEnrollment is planned for November 2018.

Different Effects of Oral Contraceptive and Dydrogesterone Treatment on Oxidative Stress Levels in Premenopausal Women.

BackgroundThe aim of the study was to observe the changes in blood oxidative stress levels by oral contraceptive (OC) and/or dydrogesterone (DG) treatment.MethodsA retrospective cohort of 27 premenopausal women with primary dysmenorrhea consisted of the OC treatment group (N = 17) and the DG treatment group (N = 10) by choice of the initial treatment. The OC group included two subgroups: patients with continuous OC treatment (treated for at least 15 months, N = 10) and patients with discontinuous OC treatment (switched to DG treatment after approximately 6 months of initial OC treatment: N = 7). The DG group had 15 months of continuous DG treatment. Blood parameters, including diacron-reactive oxygen metabolites (d-ROMs: an oxidative stress marker), were measured.ResultsThe d-ROMs level was elevated in the OC group 3 months after initial treatment (mean: from 321 (at baseline) to 512 Carratelli Units (Carr U); P < 0.01), while such changes were not observed in the DG group. The d-ROMs level was reduced in the discontinuous OC subgroup 15 months after initial treatment (from 508 (3 months after initial treatment) to 372 Carr U; P < 0.01), while such changes were not observed in the continuous OC subgroup. The DG group displayed unchanged the d-ROMs level.ConclusionReplacing OC with DG can attenuate oxidative stress as elevated by OC, thereby alleviating the possible vascular risks with OC treatment.

Premenstrual Dysphoric Disorder: Contemporary Diagnosis and Management

Most ovulatory women experience premenstrual symptoms (premenstrual syndrome, molimina) which indicate impending menstruation and are of little clinical relevance because they do not affect quality of life. A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships. The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials. Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women. Pharmacotherapies (particularly selective serotonin reuptake inhibitors and SNRIs) represent the first-line treatment for premenstrual dysphoric disorder and severe, mood-related premenstrual syndrome. Continuous combined oral contraceptives have limited evidence for usefulness in premenstrual dysphoric disorder, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate first-line treatments (e.g., selective serotonin reuptake inhibitors). The use of cognitive behavioural therapies is promising, but it remains limited by sparse data and restricted access to trained professionals. A proper diagnosis (particularly the distinction from other underlying psychiatric conditions) is crucial for the implementation of effective therapy and alleviation of this impairing condition.

P18.09: Retzius' retroperitoneal bladder endometriosis: a new entity of an enigmatic disease

To report Retzius' space retroperitoneal bladder deep infiltrating endometriosis (DIE), a new and unusual anatomic site which makes challenging both the diagnosis than the surgical treatment. Consecutive fertile women with DIE complaining endometriosis-related urinary symptoms were prospectively enrolled. 3D- transvaginal sonography (TVS) was performed in all patients with the GE Voluson E8 unit, using a wide-band 3-9 MHz transducer. 3D-TVS was performed with a properly strict methodology as diagnostic tool, based on a properly mid-filled bladder volume (100-150 mL). VCI analysis by 2mm slices of the stored 3D multiplanar examinations was considered for the evaluation of bladder nodules. Surgery was based on laparoscopic management of retroperitoneal bladder DIE, medical treatment on continuous oral contraceptives (COC). Demographic, medical, imaging and surgical data were recorded. Eight patients were enrolled. Median age was 34 years (range 24-43) years. Retroperitoneal bladder endometriotic nodules typically appear as ventral smooth, hypoechoic, homogeneous oval-shaped lesions. Laparoscopic surgery, performed in two cases, showed negative peritoneal findings, with the need to approach to the Retzius space in combination with a transurethral endoscopic approach and/or transrectal sonography to intra-operatively identify otherwise macroscopically normal appearance bladder wall. Medical therapy by COC permitted to control pain in most of symptomatic patients. 3D-TVS confirmed to be the standard technique to investigate patients complaining DIE-related urinary symptoms. Laparoscopic surgery might be incomplete because of negative peritoneal findings. A combined transurethral endoscopic and/or transrectal sonographic approach is a safe and easy technique for the management of Retzius' space retroperitoneal bladder DIE, with low risks and good resolution of symptoms.

Endometriosis, an everlasting challenge.

Endometriosis, an everlasting challenge.

Combined oral contraceptive treatment for bleeding complaints with the etonogestrel contraceptive implant: a randomised controlled trial

Objective: Estimate symptom improvement rate of women with bleeding complaints using the etonogestrel contraceptive implant when started on continuous combined oral contraceptives (COC).Methods: We conducted a double-blinded randomised controlled trial of women reporting troublesome bleeding related to their etonogestrel contraceptive implant and desiring intervention. Participants received continuous COCs or placebo for four weeks to evaluate self-reported bleeding improvement at four weeks. Participants could continue study treatment or prescribed COCs for another eight weeks if desired. We planned to enroll 130 participants between two sites (80% power to detect a 20% effect size at a 0.05 significance level, with 10% loss to follow up).Results: We closed the study after enrolling 26 participants due to recruitment futility. All women on COCs and 75% of placebo users reported bleeding improvement at four weeks (p = 0.09), with 92% and 42%, respectively, reporting significant improvement (p = 0.03). The median number of days until bleeding stopped for at least four days in COC and placebo users was 1 day (range 1–9) and 4.5 days (range 1–28), respectively (p = 0.63). Eight (75%) COC and five (42%) placebo users opted to continue study treatment (p = 0.41). Despite bleeding improvement, women who desired implant removal at enrollment were more likely to re-request removal than those who initially considered other interventions (3 of 5 [60%] vs 1 of 17 [6%], p = 0.03).Conclusion: Although women who have troublesome bleeding while using the contraceptive implant may experience improvement with no treatment over 4 weeks, women using COCs are more likely to report significant improvement.Clinicaltrials.gov registration number: NCT01963403.

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS.

In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). Live birth, pregnancy loss, and ovulation were measured. In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.