Publications by authors named "Sven O Skouby"

47 Publications

What is the optimal luteal support in assisted reproductive technology?

Horm Mol Biol Clin Investig 2021 Feb 18. Epub 2021 Feb 18.

Department of Gynaecology and Obstetrics, Unit of Reproductive Medicine, Herlev/Gentofte Hospital, University of Copenhagen, HerlevDenmark.

The need for luteal phase support in IVF/ICSI is well established. A large effort has been made in the attempt to identify the optimal type, start, route, dosage and duration of luteal phase support for IVF/ICSI and frozen embryo transfer. These questions are further complicated by the different types of stimulation protocols and ovulation triggers used in ART. The aim of this review is to supply a comprehensive overview of the available types of luteal phase support, and the indications for their use.A review of the literature was carried out in the effort to find the optimal luteal phase support regimen with regards to pregnancy related outcomes and short and long term safety.The results demonstrate that vaginal, intramuscular, subcutaneous and rectal progesterone are equally effective as luteal phase support in IVF/ICSI. GnRH agonists and oral dydrogesterone are new and promising treatment modalities but more research is needed. hCG and estradiol are not recommended for luteal phase support. More research is needed to establish the most optimal luteal phase support in frozen embryo transfer cycles, but progesterone has been shown to improve live birth rate in some studies. Luteal phase support should be commenced between the evening of the day of oocyte retrieval, and day three after oocyte retrieval and it should be continued at least until the day of positive pregnancy test.So, in conclusion still more large and well-designed RCT's are needed to establish the most optimal luteal phase support in each stimulation protocol, and especially in frozen embryo transfer.
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http://dx.doi.org/10.1515/hmbci-2020-0081DOI Listing
February 2021

Identification of a unique epigenetic profile in women with diminished ovarian reserve.

Fertil Steril 2021 03 4;115(3):732-741. Epub 2020 Dec 4.

Department of Obstetrics and Gynaecology, Department of Reproductive Medicine, Hospital Herlev, Copenhagen University, Copenhagen, Denmark.

Objective: To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve.

Design: Prospectively collected material from a multicenter cohort of women undergoing fertility treatment.

Setting: Private and university-based facilities for clinical services and research.

Patient(s): One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC.

Intervention(s): None.

Main Outcome Measure(s): Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations.

Result(s): Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485).

Conclusion(s): The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.009DOI Listing
March 2021

Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial.

BMJ 2020 08 5;370:m2519. Epub 2020 Aug 5.

Fertility Clinic, Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Hvidovre, Kettegaard Allé 30, Copenhagen DK-2650, Denmark.

Objective: To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.

Design: Multicentre, randomised controlled superiority trial.

Setting: Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.

Participants: 460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.

Interventions: Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.

Main Outcome Measures: The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.

Results: Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.

Conclusions: In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.

Trial Registration: Clinicaltrials.gov NCT02746562.
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http://dx.doi.org/10.1136/bmj.m2519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399608PMC
August 2020

Purified and specific cytoplasmic pollen extract: a non-hormonal alternative for the treatment of menopausal symptoms.

Gynecol Endocrinol 2020 Mar 5;36(3):190-196. Epub 2020 Feb 5.

Palacios Institute of Women's Health, Madrid, Spain.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin may also be a suitable option for the management of menopausal symptoms in women with breast cancer.
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http://dx.doi.org/10.1080/09513590.2020.1722994DOI Listing
March 2020

Effect of Dosage of 17ß-Estradiol on Uterine Growth in Turner Syndrome-A Randomized Controlled Clinical Pilot Trial.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C, Denmark.

Context: Most Turner syndrome (TS) girls need exogenous estrogen treatment to induce puberty and normal uterine growth. After puberty, the optimal estrogen treatment protocol has not been determined.

Objective: To compare 2 doses of oral 17ß-estradiol on uterine size.

Design: A double-blind, 5-year randomized controlled clinical trial.

Setting: Ambulatory care.

Participants: Twenty young TS women (19.2 ± 2.5 years, range 16.0-24.9) participated. Sixteen patients completed the study. No patients withdrew due to adverse effects.

Intervention: The lower dose (LD) group took 2 mg 17ß-estradiol/d orally and placebo. The higher dose (HD) group took 4 mg 17ß-estradiol/d orally.

Main Outcome Measure(s): Uterine volume evaluated by transabdominal ultrasound yearly.

Results: Uterine size increased significantly more in the HD group compared with the LD group (P = 0.038), with a gain in uterine volume within the first 3 years of treatment of 19.6 mL (95% confidence interval [CI] = 4.0-19.0) in the HD group compared with 11.5 mL (95% CI = 11.2-27.9) in the LD group. The difference in 3-year gain was 8.1 mL (95% CI = 0.7-15.9). At the last visit, there were no significant differences in uterine volume between the groups.

Conclusion: HD oral 17ß-estradiol induces a steeper increase in uterine volume within the first years of treatment compared with the LD. However, the uterine growth potential seems to be the same in most young TS women making the duration of treatment equally significant as estrogen dose, although a few TS women did not experience sufficient uterine growth on 2 mg of estradiol.

Clinicaltrials.gov: NCT00134745Abbreviations: BMI, body mass index; BSA, body surface area; DHEAS, dihydroepiandrosteronesulfate; HD, higher dose; HRT, hormone replacement therapy; LD, lower dose; TS, Turner syndrome; US, ultrasound.
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http://dx.doi.org/10.1210/clinem/dgz061DOI Listing
March 2020

Impact of progestogens on hemostasis.

Horm Mol Biol Clin Investig 2018 Nov 17;37(2). Epub 2018 Nov 17.

Unit for Thrombosis Research, Institute of Regional Health Research, Faculty of Health Science, University of Southern Denmark and Department of Clinical Biochemistry, Hospital of Southwest Denmark, Esbjerg, Denmark.

Combined hormonal contraception containing estrogen and progestogen and postmenopausal hormone therapy with estrogen ± progestogen are reported risk factors for venous thrombosis. The thrombotic risk varies by estrogen dose and type of progestogen. Estrogen combined with "newer generation" progestogens in combined oral contraceptives may have higher thrombotic risk than estrogen combined with older generation progestogens. Among postmenopausal women thrombotic risk also varies by type of hormone and mode of delivery. Although the risk of thrombosis with the different hormonal compounds is uncertain, it has definitely been attributed to the pharmacological effect of the hormones on hemostasis. Animal and cell culture studies have demonstrated the pharmacodynamics of progestogens with respect to hemostasis. Extrapolation from these studies to clinical conditions and further to clinical end points such as cardiovascular disease is, however, controversial. Few clinical studies have focused on the effect of progestogen only therapy on the hemostatic system in vivo. Most of the current knowledge regarding the in vivo effect of progestogens on hemostasis is obtained from studies with combined contraceptives. These results obviously reflect the combined influence of both estrogen and progestogen on hemostasis, and extrapolation to progestogen-only conditions is challenging. This paper discusses the pharmacodynamics of progestogens in relation to the hemostatic system, addressing results obtained in animal and cell culture studies and in clinical studies employing progestogen-only and combined oral contraceptives. The compiled results suggest that the major effect of progestogens on hemostasis is related to alterations in platelet function and the tissue factor pathway of coagulation. More studies focusing on these topics are warranted.
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http://dx.doi.org/10.1515/hmbci-2018-0041DOI Listing
November 2018

Effect of liraglutide on atrial natriuretic peptide, adrenomedullin, and copeptin in PCOS.

Endocr Connect 2018 Jan;7(1):115-123

Department of Internal MedicineCenter of Endocrinology and Metabolism, Herlev Gentofte Hospital, Copenhagen, Denmark.

Context: Women with polycystic ovary syndrome (PCOS) have an increased risk of cardiovascular disease (CVD), and biomarkers can be used to detect early subclinical CVD. Midregional-pro-adrenomedullin (MR-proADM), midregional-pro-atrial natriuretic peptide (MR-proANP) and copeptin are all associated with CVD and part of the delicate system controlling fluid and hemodynamic homeostasis through vascular tonus and diuresis. The GLP-1 receptor agonist liraglutide, developed for treatment of type 2 diabetes (T2D), improves cardiovascular outcomes in patients with T2D including a decrease in particular MR-proANP.

Objective: To investigate if treatment with liraglutide in women with PCOS reduces levels of the cardiovascular biomarkers MR-proADM, MR-proANP and copeptin.

Methods: Seventy-two overweight women with PCOS were treated with 1.8 mg/day liraglutide or placebo for 26 weeks in a placebo-controlled RCT. Biomarkers, anthropometrics, insulin resistance, body composition (DXA) and visceral fat (MRI) were examined.

Results: Baseline median (IQR) levels were as follows: MR-proADM 0.52 (0.45-0.56) nmol/L, MR-proANP 44.8 (34.6-56.7) pmol/L and copeptin 4.95 (3.50-6.50) pmol/L. Mean percentage differences (95% CI) between liraglutide and placebo group after treatment were as follows: MR-proADM -6% (-11 to 2,  = 0.058), MR-proANP -25% (-37 to -11,  = 0.001) and copeptin +4% (-13 to 25,  = 0.64). Reduction in MR-proANP concentration correlated with both increased heart rate and diastolic blood pressure in the liraglutide group. Multiple regression analyses with adjustment for BMI, free testosterone, insulin resistance, visceral fat, heart rate and eGFR showed reductions in MR-proANP to be independently correlated with an increase in the heart rate.

Conclusion: In an RCT, liraglutide treatment in women with PCOS reduced levels of the cardiovascular risk biomarkers MR-proANP with 25% and MR-proADM with 6% (borderline significance) compared with placebo. The decrease in MR-proANP was independently associated with an increase in the heart rate.
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http://dx.doi.org/10.1530/EC-17-0327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754509PMC
January 2018

Comparison of a 'freeze-all' strategy including GnRH agonist trigger versus a 'fresh transfer' strategy including hCG trigger in assisted reproductive technology (ART): a study protocol for a randomised controlled trial.

BMJ Open 2017 Jul 31;7(7):e016106. Epub 2017 Jul 31.

Department of Obstetrics and Gynaecology, The Fertility Clinic, Hvidovre University Hospital, Copenhagen, Denmark.

Introduction: Pregnancy rates after frozen embryo transfer (FET) have improved in recent years and are now approaching or even exceeding those obtained after fresh embryo transfer. This is partly due to improved laboratory techniques, but may also be caused by a more physiological hormonal and endometrial environment in FET cycles. Furthermore, the risk of ovarian hyperstimulation syndrome is practically eliminated in segmentation cycles followed by FET and the use of natural cycles in FETs may be beneficial for the postimplantational conditions of fetal development. However, a freeze-all strategy is not yet implemented as standard care due to limitations of large randomised trials showing a benefit of such a strategy. Thus, there is a need to test the concept against standard care in a randomised controlled design. This study aims to compare ongoing pregnancy and live birth rates between a freeze-all strategy with gonadotropin-releasing hormone (GnRH) agonist triggering versus human chorionic gonadotropin (hCG) trigger and fresh embryo transfer in a multicentre randomised controlled trial.

Methods And Analysis: Multicentre randomised, controlled, double-blinded trial of women undergoing assisted reproductive technology treatment including 424 normo-ovulatory women aged 18-39 years from Denmark and Sweden. Participants will be randomised (1:1) to either (1) GnRH agonist trigger and single vitrified-warmed blastocyst transfer in a subsequent hCG triggered natural menstrual cycle or (2) hCG trigger and single blastocyst transfer in the fresh (stimulated) cycle. The primary endpoint is to compare ongoing pregnancy rates per randomised patient in the two treatment groups after the first single blastocyst transfer.

Ethics And Dissemination: The study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committees in Denmark and Sweden. The results of the study will be publically disseminated.

Trial Registration Number: NCT02746562; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-016106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642760PMC
July 2017

Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial.

Diabetes Obes Metab 2018 01 11;20(1):215-218. Epub 2017 Aug 11.

Department of Internal Medicine, Center of Endocrinology and Metabolism, Herlev Gentofte Hospital, Copenhagen, Denmark.

Women with polycystic ovary syndrome (PCOS) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT) and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled, randomized clinical trial 72 women with PCOS, with a BMI > 25 kg/m and/or insulin resistance, were treated with liraglutide or received placebo 1.8 mg/d (2:1) for 26 weeks. Liver fat content was assessed by HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD by two-thirds (all P < .01). Sex-hormone-binding-globulin (SHBG) levels increased by 19% (P = .03), and free testosterone decreased by 19% (P = .054). HbA1c, fasting glucose and leptin were reduced (all: P < .05), whereas measures of insulin resistance, adiponectin and glucagon did not change. In conclusion, 26 weeks of liraglutide treatment in PCOS resulted in significant reductions in liver fat content, VAT and the prevalence of NAFLD.
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http://dx.doi.org/10.1111/dom.13053DOI Listing
January 2018

Quantification of visceral adipose tissue in polycystic ovary syndrome: dual-energy X-ray absorptiometry versus magnetic resonance imaging.

Acta Radiol 2018 Jan 23;59(1):13-17. Epub 2017 May 23.

1 Center of Endocrinology and Metabolism, Dept. of Internal medicine, Herlev Gentofte Hospital, Denmark.

Background Polycystic ovary syndrome (PCOS) is associated with frequent overweight and abdominal obesity. Quantifying visceral adipose tissue (VAT) in PCOS patients can be a tool to assess metabolic risk and monitor effects of treatment. The latest dual-energy X-ray absorptiometry (DXA) technology can measure VAT and subcutaneous adipose tissue (SAT) in a clinical setting. Purpose To compare DXA-measurements of VAT and SAT with the gold standard MRI in women with PCOS. Material and Methods A cross-sectional study of 67 overweight women with PCOS was performed. Measurements of VAT and SAT were performed by DXA in a 5-cm thick transverse slice at the L4/L5 level and by MRI in a 1-cm thick transverse slice at the L3 level. Results Mean (SD) DXA-VAT was 81 (34) cm, DXA-SAT was 498 (118) cm, MRI-VAT was 117 (48) cm, and MRI-SAT was 408 (122) cm. MRI and DXA measures of VAT (r = 0.82, P < 0.001) and SAT (r = 0.92, P < 0.001) correlated closely, and DXA-VAT was stronger correlated with MRI-VAT than BMI (r = 0.62, P < 0.001) and waist circumference (r = 0.60, P < 0.001). DXA-VAT coefficient of variance was 6.7% and inter correlation coefficient was 0.98. Bland-Altman analyses showed DXA to slightly underestimate VAT and SAT measurements compared with MRI. Conclusion DXA and MRI measurements of VAT and SAT correlated closely despite different size of region of interest, and DXA-VAT was superior to waist circumference and BMI in estimating MRI-VAT. DXA showed high reproducibility making it is suitable for repeated measurements in the same individual over time.
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http://dx.doi.org/10.1177/0284185117711475DOI Listing
January 2018

Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial.

Reprod Biomed Online 2017 Jul 24;35(1):121-127. Epub 2017 Apr 24.

Department of Obstetrics and Gynecology, Herlev Gentofte Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.

Polycystic ovary syndrome (PCOS) encompasses an ovarian and a metabolic dysfunction. Glucagon-like peptide-1 (GLP-1) analogues facilitate weight loss and ameliorate metabolic dysfunction in overweight women with PCOS, but their effect on ovarian dysfunction is scarcely reported. In a double-blind, randomized trial, 72 women with PCOS were allocated to intervention with the GLP-1 analogue liraglutide or placebo (1.8 mg/day), in a 2:1 ratio. At baseline and 26-week follow-up, bleeding pattern, levels of AMH, sex hormones and gonadotrophins were assessed and ovarian morphology evaluated. Liraglutide caused 5.2 kg (95% CI 3.0 to 7.5, P < 0.0001) weight loss compared with placebo. Bleeding ratio improved with liraglutide: 0.28 (95% CI 0.20 to 0.36, P < 0.001); placebo: 0.14 (95% CI 0.02 to 0.26, P < 0.05); between-group difference: 0.14 (95% CI 0.03 to 0.24, P < 0.05). In the liraglutide group, SHBG increased by 7.4 nmol/L (95% CI 4.1 to 10.7) and free testosterone decreased by 0.005 nmol/L (95% CI -0.009 to -0.001). Ovarian volume decreased by -1.6 ml (95% CI -3.3 to 0.1) with liraglutide versus placebo. Nausea and constipation were more prevalent in the liraglutide group. Liraglutide improved markers of ovarian function in overweight women with PCOS, and might be a possible intervention.
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http://dx.doi.org/10.1016/j.rbmo.2017.03.023DOI Listing
July 2017

Safety after extended repeated use of ulipristal acetate for uterine fibroids.

PLoS One 2017 7;12(3):e0173523. Epub 2017 Mar 7.

University of Edinburgh, Department of Pathology Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Objective: To assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters.

Methods: This long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety.

Results: All data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10-18 days after the start of menses following treatment courses 5-8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush.

Conclusion: The results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340384PMC
August 2017

Liraglutide in polycystic ovary syndrome: a randomized trial, investigating effects on thrombogenic potential.

Endocr Connect 2017 Feb 24;6(2):89-99. Epub 2017 Jan 24.

Department of Obstetrics and GynecologyHerlev Gentofte Hospital, Herlev, Denmark.

Polycystic ovary syndrome (PCOS) is associated with increased risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) in later life. We aimed to study the effect of liraglutide intervention on markers of VTE and CVD risk, in PCOS. In a double-blind, placebo-controlled, randomized trial, 72 overweight and/or insulin-resistant women with PCOS were randomized, in a 2:1 ratio, to liraglutide or placebo 1.8 mg/day. Endpoints included between-group difference in change (baseline to follow-up) in plasminogen activator inhibitor-1 levels and in thrombin generation test parameters: endogenous thrombin potential, peak thrombin concentration, lag time and time to peak. Mean weight loss was 5.2 kg (95% CI 3.0-7.5 kg,  < 0.001) in the liraglutide group compared with placebo. We detected no effect on endogenous thrombin potential in either group. In the liraglutide group, peak thrombin concentration decreased by 16.71 nmol/L (95% CI 2.32-31.11,  < 0.05) and lag time and time to peak increased by 0.13 min (95% CI 0.01-0.25,  < 0.05) and 0.38 min (95% CI 0.09-0.68,  < 0.05), respectively, but there were no between-group differences. There was a trend toward 12% (95% CI 0-23,  = 0.05) decreased plasminogen activator inhibitor-1 in the liraglutide group, and there was a trend toward 16% (95% CI -4 to 32,  = 0.10) reduction, compared with placebo. In overweight women with PCOS, liraglutide intervention caused an approximate 5% weight loss. In addition, liraglutide affected thrombin generation, although not significantly differently from placebo. A concomitant trend toward improved fibrinolysis indicates a possible reduction of the baseline thrombogenic potential. The findings point toward beneficial effects of liraglutide on markers of VTE and CVD risk, which should be further pursued in larger studies.
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http://dx.doi.org/10.1530/EC-16-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424770PMC
February 2017

Atrial natriuretic peptide, copeptin and adrenomedullin levels in polycystic ovary syndrome: a case-control study.

Gynecol Endocrinol 2017 Jan 16;33(1):30-33. Epub 2016 Jul 16.

a Department of Internal Medicine , Division of Endocrinology , and.

Background: Polycystic ovary syndrome (PCOS) defined by the Rotterdam criteria does not take into account the unhealthy metabolic profile of the syndrome with increased insulin resistance (IR) and overweight favoring development of type 2 diabetes, hypertension and cardiovascular disease (CVD). We assess three vasoactive peptides associated with CVD in women with PCOS.

Method: Plasma levels of mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin and mid-regional pro-adrenomedullin (MR-proADM) were measured in 98 PCOS patients and 46 age- and BMI-matched healthy women.

Results: We found no difference in levels of MR-proANP, copeptin and MR-proADM between the PCOS and control group. Multiple regression analyses on a combined group of PCOS and control subjects demonstrated an inverse correlation between MR-proANP and IR (measured by fasting C-peptide) and a positive correlations between copeptin and IR as well as MR-proADM and BMI. We found no association between peptide levels and different Rotterdam phenotypes.

Conclusion: Plasma concentrations of MR-proANP, copeptin and MR-proADM were not increased in PCOS compared to age- and BMI-matched controls. Thus, these peptides cannot be used to detect increased risk of CVD in a young PCOS cohort.
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http://dx.doi.org/10.1080/09513590.2016.1202915DOI Listing
January 2017

Menopause weight gain: the influence of TSEC intervention.

Authors:
Sven O Skouby

Menopause 2016 Apr;23(4):357-8

Endocrinological and Reproductive Unit, Department of Obstetrics and Gynecology, Herlev/Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1097/GME.0000000000000623DOI Listing
April 2016

Ovarian morphology in polycystic ovary syndrome: estimates from 2D and 3D ultrasound and magnetic resonance imaging and their correlation to anti-Müllerian hormone.

Acta Radiol 2017 Aug 13;58(8):997-1004. Epub 2016 Nov 13.

1 Department of Obstetrics and Gynecology, Herlev Gentofte Hospital, Herlev, Denmark.

Background Due to improved ultrasound scanners, new three-dimensional (3D) modalities, and novel Anti-Müllerian hormone (AMH)-assays, the ultrasound criteria for polycystic ovarian morphology are under debate and the appropriate thresholds are often requested. Purpose To quantify the differences in estimates of ovarian volume and antral follicle count (AFC) from two-dimensional (2D) and 3D transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI). Material and Methods A cross-sectional study on 66 overweight women with polycystic ovary syndrome (PCOS) according to Rotterdam criteria. Ovarian volume and AFC were estimated from MRI, 2D TVUS, and 3D TVUS, and serum AMH levels were assessed. Bland-Altman statistics were used for comparison. Results Participants had a median age of 29 years (age range, 19-44 years) with a mean BMI of 32.7 kg/m (SD 4.5). Ovarian volume from 2D TVUS was 1.48 mL (95% confidence interval [CI], 0.94-2.03; P < 0.001) and 1.25 mL (95% CI, 0.62-1.87; P < 0.001) smaller than from 3D TVUS and MRI, respectively. AFC from 2D TVUS was 18% (95% CI, 13-23; P < 0.005) and 16% (95% CI, 6-25; P < 0.005) smaller than estimates from 3D TVUS and MRI, respectively. Correlations between AMH and AFC from 2D TVUS, 3D TVUS, and MRI were 0.67, 0.78, and 0.70, respectively ( P < 0.001 for all). Conclusion In an overweight PCOS population, 2D TVUS underestimated ovarian volume and AFC as compared with 3D TVUS and MRI. Serum AMH correlated best with AFC from 3D TVUS, followed by MRI and 2D TVUS. The advantage of 3D TVUS might be of minor clinical importance when diagnosing PCOS, but useful when the actual AFC are of interest, e.g. in fertility counseling and research.
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http://dx.doi.org/10.1177/0284185116676656DOI Listing
August 2017

Endogenous thrombin potential in polycystic ovary syndrome: the association to body mass index, insulin resistance, and inflammation.

Gynecol Endocrinol 2015 17;31(9):720-4. Epub 2015 Aug 17.

a Department of Gynaecology and Obstetrics, Faculty of Health and Medical Sciences , Herlev University Hospital, Copenhagen University , Herlev , Denmark .

Objectives: The objective of this study is to investigate plasma endogenous thrombin generation in four different phenotypes of polycystic ovary syndrome (PCOS) defined by Body Mass Index (BMI) and insulin resistance (IR). PCOS is diagnosed according to the Rotterdam criteria.

Design: Multicenter cross-sectional study.

Setting: Two major University Hospitals in the Capital region of Denmark.

Patients: Hundred forty-eight European women with PCOS were consecutively recruited during April 2010-February 2012. Clinical examination, blood sampling, and DEXA scan were performed.

Main Outcome Measures: Endogenous thrombin potential (ETP).

Results: PCOS women with phenotype BMI > 25 + IR have increased potential of thrombin generation. ETP is associated with total body fat mass, IR, and CRP.

Conclusions: Obese and insulin resistant women with PCOS have elevated level of ETP corresponding to increased risk of CVD. ETP is related to well-known CVD risk factors in PCOS but not in general to the Rotterdam criteria.
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http://dx.doi.org/10.3109/09513590.2015.1032930DOI Listing
August 2016

Polycystic ovary syndrome: cardiovascular risk factors according to specific phenotypes.

Acta Obstet Gynecol Scand 2015 Oct 18;94(10):1082-9. Epub 2015 Jul 18.

Department of Gynecology and Obstetrics, Faculty of Health and Medical Sciences, Copenhagen University, Herlev University Hospital, Herlev, Denmark.

Introduction: Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance. The objective of this cross-sectional study was to investigate the impact of insulin resistance and body mass index (BMI) on inflammatory and hemostatic variables associated with long-term risk of cardiovascular disease in women with PCOS.

Material And Methods: 149 premenopausal women with PCOS were recruited consecutively from April 2010 to February 2012 at three Danish University Hospitals. The study was conducted at the Department of Gynecology and Obstetrics, Herlev University Hospital, Denmark. PCOS was diagnosed in accordance with the Rotterdam criteria and the women were classified into four phenotypes according to BMI and insulin resistance measured by the homeostasis model assessment of insulin resistance index. Body composition was determined by dual-energy X-ray absorptiometry. Main outcome measures were the biomarkers C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), and von Willebrand factor antigen.

Results: Normal weight insulin-resistant PCOS women were characterized by abdominal obesity and elevated levels of plasma PAI-1. Overweight/obese insulin-resistant PCOS women had increased levels of both PAI-1 and CRP. Of the three Rotterdam criteria, only hyperandrogenemia was significantly associated with the hemostatic risk marker of long-term cardiovascular disease risk.

Conclusions: Surrogate risk markers for cardiovascular disease are elevated in women with PCOS, especially insulin-resistant and overweight/obese women.
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http://dx.doi.org/10.1111/aogs.12706DOI Listing
October 2015

Effects of conjugated estrogens/bazedoxifene on lipid and coagulation variables: a randomized placebo- and active-controlled trial.

Menopause 2015 Jun;22(6):640-9

From the 1Department of Obstetrics and Gynecology, Herlev Hospital, Copenhagen University Hospital, Denmark; 2Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; and 3Pfizer Inc, Collegeville, PA.

Objective: This study aims to evaluate the effects of conjugated estrogens (CE)/bazedoxifene (BZA) on lipid and coagulation variables in a randomized, double-blind, placebo- and active-controlled phase 3 study of nonhysterectomized postmenopausal women.

Methods: The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial evaluated the efficacy and safety of CE/BZA in postmenopausal women (N = 1,843) with menopausal symptoms. Lipid (N = 1,843) and coagulation (N = 590) variables were assessed in women receiving daily CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or placebo for 12 months.

Results: At 12 months, CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, BZA 20 mg, and CE 0.45 mg/MPA 1.5 mg decreased total cholesterol and low-density lipoprotein cholesterol compared with placebo (P < 0.01 for all). Both CE/BZA doses and CE/MPA increased high-density lipoprotein cholesterol compared with placebo (P < 0.05 for all). CE 0.45 mg/BZA 20 mg had a neutral effect on triglycerides; CE 0.625 mg/BZA 20 mg and CE/MPA increased triglycerides compared with placebo (P < 0.05). Both CE/BZA doses were associated with small but significant effects on hemostasis variables, including reductions in antithrombin, plasminogen activator inhibitor-1, and fibrinogen activity, and an increase in plasminogen activity relative to placebo at 12 months. Incidences of cardiovascular and venous thromboembolic events were similar among treatment groups.

Conclusions: This study provides reassurance that CE/BZA does not adversely affect lipid metabolism or hemostatic balance. In accordance, the incidences of venous thromboembolic events and cardiovascular events in postmenopausal women are similar to those observed with placebo.
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http://dx.doi.org/10.1097/GME.0000000000000362DOI Listing
June 2015

An overview of four studies of a continuous oral contraceptive (levonorgestrel 90 mcg/ethinyl estradiol 20 mcg) on premenstrual dysphoric disorder and premenstrual syndrome.

Contraception 2012 May 5;85(5):437-45. Epub 2011 Dec 5.

Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.

Background: This article presents an overview of four studies that evaluated a continuous oral contraceptive (OC) containing levonorgestrel (90 mcg) and ethinyl estradiol (20 mcg; LNG/EE) for managing premenstrual dysphoric disorder (PMDD) and premenstrual syndrome (PMS).

Study Design: Three randomized, double-blind, placebo-controlled trials and one open-label, single-treatment substudy examined mean changes from baseline in the Daily Record of Severity of Problems (DRSP) or Penn Daily Symptom Rating (DSR).

Results: Improvements from baseline in mean DRSP and DSR scores were observed, but results were not consistent among the studies. Mean percent improvement of premenstrual symptoms ranged from 30% to 59% in controlled trials and 56% to 81% in an open-label substudy. A large placebo effect was also observed in the placebo-controlled studies. Continuous LNG/EE yielded a favorable safety profile.

Conclusions: These data, although not consistent, indicate that continuous LNG/EE may reduce the symptoms of PMDD and PMS, providing an option for women who are appropriate candidates for a continuous OC as a contraceptive, the approved indication for this medication.
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http://dx.doi.org/10.1016/j.contraception.2011.09.010DOI Listing
May 2012

Normal tempo of bone formation in Turner syndrome despite signs of accelerated bone resorption.

Horm Res Paediatr 2011 26;76(3):193-201. Epub 2011 Jul 26.

Department of Pediatrics, Hillerød Hospital, Denmark.

Aims: To evaluate area bone mineral density (aBMD) and volumetric BMD (vBMD) by dual-energy X-ray absorptiometry, and relations to bone markers and hormones in adolescent women with Turner syndrome (TS).

Methods: Cross-sectional study in TS patients (n = 37, 16.7 ± 3.4 years) and control group (n = 49), assessed by dual-energy X-ray absorptiometry, bone markers and hormones. TS patients were divided into a young group receiving ('ongoing') GH (n = 15) and an older group previously receiving ('previous') GH (n = 22).

Results: vBMD(spine) was similar in 'ongoing GH' TS, but higher in 'previous GH' TS, compared to controls. vBMD(hip) was lower in 'ongoing GH' TS, but similar in 'previous GH'. z scores for aBMD were uniformly reduced in 'ongoing TS', but near-normalized in 'previous GH' TS. Bone formation and resorption markers were increased in 'ongoing GH' TS, while 'previous GH' TS had elevated bone resorption markers.

Conclusion: BMD increased in parallel with age in TS patients receiving optimal estradiol replacement therapy and GH according to consensus guidelines, and in controls. Young TS undergoing pubertal induction and still receiving GH have lower z score BMD than older TS patients receiving hormonal replacement therapy, where a near-normalization of BMD was achieved. TS patients previously receiving GH showed signs of increased bone resorption.
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http://dx.doi.org/10.1159/000329046DOI Listing
February 2012

Plasma factor VII-activating protease is increased by oral contraceptives and induces factor VII activation in-vivo.

Thromb Res 2011 Nov 6;128(5):e67-72. Epub 2011 Jul 6.

Unit for Thrombosis Research, Institute of Public Health, University of Southern Denmark, Esbjerg, Denmark.

Unlabelled: Oral contraceptive (OC) use influences the hemostatic system significantly and is a risk factor for development of cardiovascular disease. Factor VII-activating protease (FSAP) has potential effects on hemostasis. The 1601GA genotype of the 1601G/A polymorphism in the FSAP gene expresses a FSAP alloenzyme with reduced pro-fibrinolytic activity. Presently, we address whether OC use and OC formulation affect FSAP measures in human blood. Healthy women (n=588) were allocated to six cycles of OCs with estrogen contents of 20 μg (n=158), 30 μg (n=284), 35 μg (n=79) or 50 μg (n=67) combined with various progestins. FSAP genotypes, FSAP and factor VII (FVII) plasma measures were assessed at baseline and after 6 cycles of OC. The 1601GA genotype was present in 49 (8.3%) of the women and was associated with significantly reduced levels of FSAP (P≤0.001). OC use increased FSAP antigen by 25% and FSAP activity by 59% (P<0.001). The FSAP increase was comparable in the seven different OC treatment groups (P>0.05). The relative increase in FSAP activity was significantly higher in women carrying the 1601GG genotype (63%) than in women carrying 1601GA genotype (50%) (P=0.01) and was associated with an increased activation of FVII.

In Conclusion: OC use increases the plasma measures of FSAP. The increase in FSAP is comparable in the seven OC-groups studied but is more significant in women carrying the 1601GG genotype than in women with the 1601GA genotype and results in increased activation of FVII suggesting that FSAP-induced activation of FVII takes place in-vivo and not only in-vitro as hitherto described.
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http://dx.doi.org/10.1016/j.thromres.2011.06.013DOI Listing
November 2011

Hormonal contraception in obesity, the metabolic syndrome, and diabetes.

Authors:
Sven O Skouby

Ann N Y Acad Sci 2010 Sep;1205:240-4

Division of Reproductive Endocrinology, Department of Gynecology and Obstetrics, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.

The rate of obesity worldwide is currently at epidemic proportions. As part of obesity, the metabolic syndrome describes a clustering of metabolic abnormalities that increase the cardiovascular and diabetes risk. In particular, women from developing countries have diabetes in the reproductive age resulting in more pregnancies where both the mother and the fetus are at high risk. Consequently, use of safe and effective contraceptive methods is of paramount importance. Paradoxically, both obese and diabetic women are less likely to use contraception as compared to women of normal weight. Modern types of hormonal contraceptives are safe and provide important noncontraceptive benefits. The impact of obesity on drug pharmacokinetics may result in lower blood levels of steroid contraceptives that reduce their ability to prevent pregnancy, but the actual change is probably minimal. In women with uncomplicated diabetes, hormonal contraception should therefore be part of the highly needed preconception care and metabolic control.
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http://dx.doi.org/10.1111/j.1749-6632.2010.05662.xDOI Listing
September 2010

Aortic dimensions in girls and young women with turner syndrome: a magnetic resonance imaging study.

Pediatr Cardiol 2010 May 10;31(4):497-504. Epub 2010 Jan 10.

Department of Paediatrics, Hillerød Hospital, 3400 Hillerød, Denmark.

This study aimed to determine the dimensions of the thoracic aorta and the predictors of aortic dimensions in girls and young women with Turner syndrome (TS). A cross-sectional study was performed at a secondary care center. The study compared 41 TS patients with 50 healthy age-matched control subjects. The mean age of the patients was 17 +/- 3.3 years. Magnetic resonance imaging was performed for all the patients. The thoracic aortic diameters of the patients were measured at nine positions. Adjustment for body surface area (BSA) was performed. The outcome for the patients was measured in terms of absolute and BSA-adjusted aortic dilation. In TS, both the absolute and the BSA-adjusted mean aortic diameters were smaller than or comparable with those of the control subjects. However, individual aortic dilation at one to four positions was found in four TS patients according to the uncorrected data and in five TS patients after BSA-adjustment. The aortic diameters correlated with height, weight, body mass index (BMI), and BSA at all positions (R = 0.34-0.60; all p < 0.04). The diameters of the aortic arch and the descending aorta correlated with a history of aortic coarctation (R = 0.35-0.52; p < 0.03). The presence of bicuspid aortic valves correlated at the descending part of the aorta (R = 0.38; p < 0.03). The mean thoracic aortic dimensions were not enlarged in girls or young TS patients. The BSA predicted aortic size at all positions. The prevalence of aortic dilation and aneurysm was lower in this population of girls and younger women with TS than in older TS populations.
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http://dx.doi.org/10.1007/s00246-009-9626-8DOI Listing
May 2010

Progestins in HRT: sufferance or desire?

Maturitas 2009 Apr 8;62(4):371-5. Epub 2009 Feb 8.

Department of Obstetrics and Gynecology, Herlev University Hospital, Faculty of Health Sciences, 63 C7F Herlev Ringvej, Herlev, Denmark.

While the benefits of progestins in hormonal replacement therapy are well recognized as far as endometrial protection is concerned the data on breast tissue and the cardiovascular system are contentious. Following the Women's Health Initiative study, the Million Women Study and The Women's International Study of Long-duration (O)estrogen after Menopause the question can be raised: When dealing with optimal hormonal therapy after the menopause, is the progestin component accepted here on sufferance or is it desired? The answer is partly made up by the fact that the recent epidemiological data may have been not only wrongly translated in relation to the clinical settings, but also to the whole class of therapies. The various progestins available for hormonal therapy exert different partial effects at cellular level according to the biochemical composition. Due to the structural differences the progestins result in a variety of tissue transforming changes as well as metabolic and hemostatic changes. Since no single test or algorithm presently serves as golden standard for all desired hormonal effects the least changes or no changes from the premenopausal physiology may often be advantageous. In our opinion targeting this goal includes a sustained desire for an estrogen/progestin combination as optimal future hormone therapy. Moreover the strategy not only includes evaluation of the specific steroidal formula, but also a titration of the dose and choosing the optimal route of administration. With special reference to cardiovascular disease this review therefore makes a plea for differentiating between the array of chemically and functionally distinct progestins used therapeutically after the menopause in combination therapy.
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http://dx.doi.org/10.1016/j.maturitas.2008.12.019DOI Listing
April 2009

Genital cancer and oral contraceptives. The good news!

Authors:
Sven O Skouby

Eur J Contracept Reprod Health Care 2008 Dec;13(4):327-9

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http://dx.doi.org/10.1080/13625180802581239DOI Listing
December 2008

Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women.

Fertil Steril 2007 Oct 4;88(4):866-78. Epub 2007 Jun 4.

Department of Obstetrics and Gynecology, Contraceptive Research and Development Program Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA.

Objective: To address the endometrial safety of tibolone.

Design: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA).

Setting: Multi-country, multi-center ambulatory care setting.

Patient(s): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women.

Intervention(s): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA.

Main Outcome Measure(s): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA.

Result(s): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized.

Conclusion(s): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.
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http://dx.doi.org/10.1016/j.fertnstert.2006.12.052DOI Listing
October 2007
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